Introduction
Cancer, which is the outcome of the body's uncontrolled cell growth and
development, is one of the main causes of mortality on a global scale [1]. Unrestricted proliferation, invasion, and
metastasis are characteristics of cancer, which arises as a consequence of a
multi-step process leading to the build-up of several genomic alterations [2]. Global cancer burden estimates are provided
by the GBD (Global Burden of Diseases) 2019 study, which was updated and enhanced
from earlier GBD cycles [3]. These predictions
varied significantly by SDI (Sociodemographic Index) quintile, illuminating cancer
burden variations around the world (3). The greatest estimated number of incident
cases in 2019 was in the high SDI quintile; whereas the highest estimated number of
deaths and DALYs (Disability-adjusted life years) were in the middle SDI quintile
[3]. The low and low-middle SDI quintiles
have seen the greatest increases in the burden of cancer over the past ten years
[3]. These projections are essential for
achieving important SDG (United Nations (UN) Sustainable Development Goals) goals
for lowering the burden of noncommunicable diseases like cancer and increasing
equity in global cancer outcomes [3].
14,61,427 incident cases of cancer were determined to be the predicted average in
India for 2022. (Crude rate:100.4 per 100,000). In India, one in nine individuals
has a lifelong risk of developing cancer. The most common cancers in men and women,
respectively, were lung and breast cancers. Lymphoma was the most common site among
children (0–14 years) with cancer (boys: 29.2%; girls:
24.2%). According to estimates, there will be 12.8% more cancer
instances in 2025 than there were in 2020 [4].
Breast cancer is a metastatic cancer that is incurable and frequently metastasizes
to remote organs such as the bone, liver, lung, and brain. A favorable outlook and
a
high survival rate can result from early diagnosis of the illness. Numerous genes
have been associated with breast cancer. Unusual proliferation, oncogene and
anti-oncogene mutations, and tumor progression are all impacted by these factors.
Breast cancer related genes 1 and 2 are two well-known anti-oncogenes that decrease
the likelihood of breast cancer (BRCA1 and BRCA2). The BRCA genes are situated on
chromosomes 13q12 and 17q21, accordingly. They both encode proteins that inhibit
tumor growth. Lack of BRCA1 causes abnormal centrosome duplication, genetic
instability, dysregulation of the cell cycle checkpoint, and ultimately apoptosis.
The human chromosome 17 long arm contains the human epidermal growth factor receptor
2, also known as c-erbB-2, an essential oncogene in breast cancer (17q12). The EGFR
gene is located on chromosome 7's short arm. In people, it is also known as
c-erbB-1 or Her1 (7p12). The EGFR protein is activated by binding to molecules like
EGF, TGF-, amphiregulin, betacellulin, and others. It is a constituent of the
tyrosine kinase family of cell surface glycoproteins. To promote cell proliferation,
invasion, angiogenesis, and cell survival against apoptosis, the PI3K, Ras-Raf-MAPK,
and JNK downstream signaling pathways of EGFR are activated. The most common and
well-known family of 17 poly (ADP-ribose) polymerase enzymes in humans is known to
heal single-strand breaks (SSBs) and double-strand breaks (DSBs). PARP-1 is also a
DNA damage sensor. The expression of PARP-1 is upregulated in cancer cell lines and
patients' tissues, according to numerous researches. Despite being primarily
found in the nucleus, researchers have also looked at PARP-1's cytosolic
distribution [5]. The DDR process involves
five pathways, and BRCA1 and PARP-1 are both crucial steps in each one. As a means
of repairing SSBs, PARP-1 employs the base excision repair mechanism. The two
complementary systems that mediate repair in the case of the more harmful DSBs are
the homologous recombination (HR) repair system, mediated among other DNA damage
agents by BRCA1, and the non-homologous end joining (NHEJ), which is more
error-prone and can also depend on PARP activity. Surprisingly, mounting evidence
supports PARP's multifaceted functions and the interaction of the repair
pathways by indicating that PARP-1 is also crucial in the HR process. A SSB will be
caused by the administration of PARP inhibitors, and HR will fix it. When this SSB
hits the replication fork, however, it will cause a DSB in the HR-deficient
(BRCA-mutated) cells. The cell will die as a result of the accumulation of DSBs
because it will result in apoptosis or mutation formation that ups the likelihood
of
getting cancer [6]. As of 2021, the US Food
and Drug Administration (FDA) and the European Medicine Agency (EMA) have approved
four PARP-1 inhibitors as anti-cancer treatments for breast or ovarian cancer [Table 1].
Table 1 FDA and EMA approved PARP1 inhibitors
|
S. No
|
PARP1 Inhibitor
|
IC50
|
Ref
|
|
1
|
Olaparib
|
13 nM
|
7
|
|
2
|
Niraparib
|
35 nM
|
7
|
|
3
|
Rucaparib
|
80 nM
|
7
|
|
4
|
Talazoparib
|
3 nM
|
7
|
Activation and the role of PARP-1
The revelation that PARP-1 is a DNA binding protein led to the hypothesis that it
might be participated in DNA rebuild [7].
When DNA damage is minimal, PARP-1 role as a survival factor, and in a multiple
DNA repair mechanisms, including base excision, single strand break, and double
strand break repair pathways, have been linked to PARP-1 ([Figs. 1] to [4]). PARP is turned on when nicks form in
DNA molecules [8]
[9]
[10]
[11]
[12]
[13]. By means of the second zinc finger domain, PARP-1 binds to
damaged DNA to create homodimers that catalyze, NAD+ is
broken down into nicotinamide and ADP-ribose. [8]
[9]. In response to
activation, PARP-1 attaches to DNA breaks., NAD+ is split
into nicotinamide and ADP-ribose moieties, and the latter is then polymerized
onto glutamic acid residues of several nucleus acceptor proteins, including
PARP-1 [9]
[11]
[12]
[13]
[14]. When DNA is only slightly damaged, PARP-1 takes part in the DNA
repair process, which allows the cell to survive [8]
[9]
[10]
[11]
[13]. However, in situations where there has been significant DNA
destructed, PARP-1 overactivation results in a drop in NAD+
and ATP levels, which causes dysfunctional cells and mortality [9]
[11]
[14]. As a result,
overactivation of PARP has been linked to the pathogenesis of numerous
illnesses, such as cerebro-vascular disease, reperfusion injury and cancer
resistance [15]. This ADP- ribose is then
used by PARP-1 to synthesis branched nucleic acid like polymers called Poly
(ADP- ribose). Covalent interactions are formed between this and nuclear
proteins like histones, topoisomerase, endonucleases, etc. [8]
[9]
[10]
[14]. A large number of PARP-1 inhibitors
have been developed as a result of the importance of PARP-1 in DNA repair as a
therapeutic target for the therapy of cancer [12]
[16]. The ability to behave
as a stand-alone therapy to eradicate cancer cells with homologous recombination
(HR) DNA repair deficiencies, such as those who have tumor suppressor gene
loss-of-function variants in either BRCA1 or BRCA2 [17]. Through BER, DNA fractures are
repaired. In addition, PARP plays in a wide range of other nuclear functions,
such as facilitating HR [18]. Base
excision repair (BER), nucleotide excision repair (NER), and mismatch repair
(MMR), which are the main mechanisms to resolve SSB, are among the at least 5
main DNA damage repair mechanisms operating in mammalian cells [18]
[19]. The two pathways for repairing DSB are homologous recombination
(HR) and nonhomologous end joining (NHEJ). A homological arrangement of
chromosomes close to the area of the damage serves as an arrangement for HR, a
high repair system, to ensure accurate restoration of the DNA sequence [13]. NHEJ joins unrelated DNA strands after
dissecting DNA damage, changing nucleotide sequences and causing gene
rearrangements as a result. It is an error-prone pathway with reduced fidelity.
DSB are damaging lesions to cells that are challenging to heal [18]
[19]. Reports that cell lines deficient in BRCA1 and BRCA2 (proteins
involved in homologous recombination (HR) repair) are extremely susceptible to
PARP-1 inhibitors resulting in cell death further highlighted the potential of
PARP inhibition within oncology. The wild-type alleles of the recognised tumour
suppressor genes BRCA1 and BRCA2 are commonly lost in the tumours of
heterozygous carriers. Breast cancer is known to be associated with both BRCA1
and BRCA2 protein abnormalities. Ovarian, prostate, and pancreatic cancers are
also more likely to affect carriers of BRCA1 and BRCA2 variants [20]. By inhibiting PARP-1, the cancer cells
are unable to repair their damaged DNA, leading to their death. PARP-1
inhibitors have shown promising results in the treatment of breast cancer,
particularly in those with BRCA mutations, which are associated with a high risk
of developing breast and ovarian cancers. These inhibitors have been approved
for use in combination with chemotherapy for the treatment of advanced ovarian
cancer and are being studied for their potential in the treatment of breast
cancer[21]
[22]. As a result of PARP-1's
crucial role in DNA damage repair, numerous small molecules that target its
catalytic domain have been created as stand-alone therapies (synthetic lethal)
or as chemo-sensitizers in combination with ionising radiation or DNA-damaging
chemotherapeutic agents to kill cancer cells that lack DNA repair mechanisms
[22]. PARP inhibitors have been used
in cancer therapy as both chemo and radio-sensitizers, more recently, have been
employed alone in treatment of tumors displaying BRCA mutations [23].
Fig. 1 Activation of PARP-1 inhibitor
Fig. 2 Function of PARP-1
Fig. 3 Function of PARP-1 and DNA repair
Fig. 4 Mechanism of PARP-1 inhibitor
Structure of PARP-1
PARP-1 is an enzyme that plays a key role in DNA repair, genomic stability, and
cell survival. It is a member of the Poly (ADP-ribose) polymerase (PARP) family
of enzymes, which are involved in cellular responses to DNA damage [8]
[9]
[10]. PARP-1 is a 116-kDA
protein that has three principal domains, the structure of PARP-1 is made up of
multiple domains, including an N-terminal DNA-binding domain, a central
catalytic domain, and a C-terminal auto-modification domain. The DNA-binding
domain helps the enzyme recognize and bind to DNA strand breaks, while the
catalytic domain contains the active site responsible for synthesizing poly
(ADP-ribose) chains. The auto-modification domain allows for the
self-modification of PARP-1, which is important for its activity and regulation
[24]. Multiple DNA repair processes,
including base excision, single strand break, and double strand break repair
pathways, have been linked to PARP-1. PARP is activated when nicks form in DNA
molecules. Through the second zinc finger domain, PARP-1 binds to damaged DNA to
generate homodimers that catalyse the cleavage of NAD+ into nicotinamide
and ADP-ribose. Then, using ADP-ribose, it creates poly (ADP-ribose), which
resembles branched nucleic acids and makes covalent bonds with nuclear proteins
including histones, topoisomerase, endonucleases, etc., [24]. Zinc finger NLS- Binds to DNA strand
breakage
Auto-modification domain- Mediates for protein-protein interaction, Catalytic
domain- Nucleic acid binding motif [24].
[Fig. 5] PARP structure and function. PARP
contains an NH2-terminal (N-term) DNA binding domain, an
auto-modification domain and a COOH-terminal (C-term) catalytic domain. Zinc
finger motifs (Zn) recognize and bind damaged DNA, activating the catalytic
function that polymerizes poly (ADP-ribose) (PAR) from
NAD+
[24]. The
function of PARP-1 is to detect and respond to DNA damage by synthesizing poly
(ADP-ribose) chains on target proteins. This process is called poly
(ADP-ribosylation) and it serves as a signal for DNA repair processes, such as
base excision repair and homologous recombination, to occur. In addition, PARP-1
also plays a role in regulating cell death by controlling the activation of
apoptosis, or programmed cell death [8]
[9]
[10]
[14].
Fig. 5 PARP structure and function
PARP-1 inhibitors in breast cancer
PARP-1 inhibitors constitute a pharmacological category of medications that have
demonstrated encouraging outcomes in the management of breast cancer,
particularly in instances when distinct genetic alterations are detectable [25]. Poly(ADP-ribose) polymerase 1 (PARP-1)
is an enzymatic protein that plays a crucial role in the process of DNA repair
[26]. In the context of cancer
treatment, PARP-1 inhibitors function by impeding the activity of this enzyme,
hence hindering its ability to carry out its reparative functions. Consequently,
this inhibition results in the accumulation of DNA damage within cancerous cells
[27]. BRCA1 and BRCA2 mutations are
widely recognized as prominent genetic alterations linked to breast cancer[28]. The presence of these mutations
hinders the functionality of DNA repair mechanisms within cells, rendering them
more vulnerable to subsequent DNA damage. PARP inhibitors exploit this
vulnerability by additionally suppressing DNA repair mechanisms, leading to the
demise of cancerous cells [29]. PARP
inhibitors have demonstrated substantial advantages in the management of breast
cancer, namely among individuals harboring BRCA1 or BRCA2 mutations, alongside
additional impairments in DNA repair mechanisms [30]. The efficacy of PARP inhibitors in the treatment of advanced
breast cancer has been substantiated by clinical trials, which have shown
significant enhancements in terms of progression-free survival and overall
survival for patients[31]. Several PARP
inhibitors that have been approved by the Food and Drug Administration (FDA) for
the treatment of breast cancer include:
Olaparib ([Fig. 6(a)]), commercially known
as "Lynparza," is a pharmacological agent classified as a PARP-1
inhibitor [32]. The oral medicine in
question has been jointly developed by AstraZeneca and Merck & Co.
(referred to as MSD internationally, except the United States and Canada). Its
primary use lies in the treatment of several forms of cancer, notably ovarian
and breast cancer, specifically targeting distinct genetic abnormalities [32]. Lynparza (Olaparib) functions by the
inhibition of PARP enzymes, specifically PARP-1, which play a crucial role in
the cellular DNA repair process [33]. The
suppression of poly(ADP-ribose) polymerase (PARP) in cancer cells with certain
genetic abnormalities, such as BRCA1 or BRCA2 mutations, or exhibiting deficits
in DNA repair pathways, results in the accumulation of DNA damage and subsequent
induction of cell death [34]. The targeted
therapeutic strategy of Olaparib is founded on the principle of synthetic
lethality, wherein cancer cells with compromised DNA repair processes are
specifically eliminated through the use of PARP inhibitors. Lynparza has been
granted approval by the U.S. Food and Drug Administration (FDA) for multiple
indications, which include: The maintenance therapy for adult individuals with
recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who
have achieved either complete or partial response after chemotherapy based on
platinum is being discussed. The maintenance therapy for adult individuals
diagnosed with advanced ovarian cancer, who exhibit a complete or partial
response to first platinum-based chemotherapy, and possess the BRCA1 or BRCA2
genetic mutation, is indicated. The focus of this study is to investigate the
therapeutic interventions for adult individuals afflicted with deleterious or
presumed detrimental germline BRCA-mutated HER2-negative metastatic breast
cancer, who have undergone prior chemotherapy treatments [35]. The focus of this study is to
investigate the therapeutic interventions for adult individuals diagnosed with
advanced ovarian cancer, specifically those with germline BRCA mutations. The
target population comprises patients who have undergone three or more rounds of
chemotherapy prior to the study. Lynparza has exhibited substantial clinical
advantages in these particular cohorts of patients, resulting in its
authorization as a focused therapeutic intervention for ovarian cancer and
breast cancer characterized by BRCA mutations. Like all medications, Lynparza
can potentially cause negative effects, therefore it is important for a skilled
healthcare provider to closely monitor its usage. Individuals who are
contemplating the use of Lynparza as a treatment option should engage in a
comprehensive discussion with their oncologist regarding the potential
advantages and disadvantages associated with this medication. This dialogue is
crucial in order to establish the most suitable course of treatment tailored to
their unique medical circumstances [36].
Fig. 6 Structure of Olaparib (a), Niraparib (b),
Talazoparib (c), and Rucaparib (d).
Niraparib ([Fig. 6(b)]), commercially
referred to as "Zejula," is a pharmacological agent classified
as a PARP-1 inhibitor [37]. The medication
in question is an oral pharmaceutical product that has been produced by the
pharmaceutical company GlaxoSmithKline (GSK). It is primarily employed in the
therapeutic management of specific forms of cancer, with a particular focus on
advanced ovarian cancer as well as recurrent ovarian, fallopian tube, or primary
peritoneal cancer [38]. Zejula (Niraparib)
functions through the inhibition of PARP-1 and other PARP enzymes, which play a
crucial role in the cellular DNA repair process [39]. The suppression of PARP in cancer cells harboring certain
genetic abnormalities, such as BRCA1 or BRCA2 mutations, or other impairments in
DNA repair pathways, results in the accumulation of DNA damage and subsequent
cellular demise [40]. The phenomenon under
discussion is commonly referred to as synthetic lethality, wherein cancer cells
exhibiting compromised DNA repair pathways are specifically targeted for
elimination through the administration of PARP inhibitors. The approval of
Zejula by the U.S. Food and Drug Administration (FDA) pertains to its use as a
maintenance treatment for adult patients who have experienced a recurrence of
epithelial ovarian, fallopian tube, or primary peritoneal cancer and have
achieved either a complete or partial response to platinum-based chemotherapy
[39]. Additionally, this medication
has been authorized for the purpose of maintaining the treatment of individuals
who have recently been diagnosed with ovarian cancer, have undergone
chemotherapy with platinum-based agents, and have exhibited either a complete or
partial response to said treatment [41].
The targeted medication known as Niraparib (Zejula) has demonstrated substantial
therapeutic advantages in several patient populations, resulting in its approval
for the treatment of ovarian cancer. For patients who have experienced a
recurrence or have recently been diagnosed with ovarian cancer, as well as those
who possess specific genetic abnormalities linked to deficits in DNA repair,
this alternative is considered indispensable. Like all medications, Zejula may
have negative effects, and its administration should be closely supervised by a
skilled healthcare professional. Individuals who are contemplating the
utilization of Zejula as a treatment option should engage in a discussion with
their oncologist regarding the potential advantages and disadvantages associated
with the drug. This dialogue is crucial in order to establish the most suitable
course of treatment tailored to their particular medical condition.
Talazoparib ([Fig. 6(c)]), commercially
marketed as "Talzenna," is a pharmacological agent classified as
a PARP-1 inhibitor [42]. The oral medicine
in question has been produced by Pfizer and is employed for the therapeutic
management of specific forms of cancer, including HER2-negative advanced breast
cancer characterized by distinct genetic alterations. Talzenna (Talazoparib)
functions in a manner akin to other inhibitors of PARP-1, effectively impeding
the enzymatic activity of PARP enzymes, specifically PARP-1, which play a
crucial role in the process of DNA repair [43]. The suppression of PARP in cancer cells harboring certain
genetic abnormalities, such as BRCA1 or BRCA2 mutations, or other impairments in
DNA repair pathways, results in the accumulation of DNA damage and subsequent
cell death [44]. Talazoparib, like to
other inhibitors of poly (ADP-ribose) polymerase (PARP), capitalizes on the
principle of synthetic lethality to specifically target cancer cells that
possess compromised DNA repair systems [45]. Talzenna has been granted approval by the U.S. Food and Drug
Administration (FDA) for the therapeutic management of adult individuals
diagnosed with metastatic breast cancer that is HER2-negative and characterized
by deleterious or suspected harmful hereditary BRCA mutations. It is imperative
that these individuals have received prior chemotherapy treatment in the
neoadjuvant, adjuvant, or metastatic context. The clinical efficacy of
talazoparib has been demonstrated in a distinct subset of patients, resulting in
its authorization as a targeted therapeutic approach for advanced breast cancer
characterized by BRCA mutations. Like all medications, Talzenna may have adverse
effects, and its use should be closely supervised by a skilled healthcare
professional. Patients who are contemplating the use of Talzenna should engage
in a discussion with their oncologist regarding the potential advantages and
disadvantages of the treatment in order to ascertain the most suitable course of
action for their individual medical condition.
Rucaparib ([Fig. 6(d)]), commercially
known as "Rubraca," is a pharmacological agent classified as a
PARP-1 inhibitor [46]. The oral medicine,
created by Clovis Oncology, has been designed for the treatment of specific
forms of cancer, notably ovarian cancer and prostate cancer, that have distinct
genetic abnormalities. Rubraca (Rucaparib) functions in a manner akin to other
inhibitors of poly (ADP-ribose) polymerase 1 (PARP-1) by impeding the enzymatic
activity of PARP enzymes, particularly PARP-1, which play a role in the repair
of DNA [47]. The suppression of PARP in
cancer cells harboring certain genetic abnormalities, such as BRCA1 or BRCA2
mutations, or other impairments in DNA repair pathways, results in the
accumulation of DNA damage and subsequent cell death [44]. Rucaparib, like to other inhibitors of
poly (ADP-ribose) polymerase (PARP), exploits the principle of synthetic
lethality to specifically target neoplastic cells that possess compromised DNA
repair pathways [48]. Rubraca has been
granted approval by the U.S. Food and Drug Administration (FDA) for many
indications, which encompass: The maintenance therapy for adult individuals with
recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who
have achieved either complete or partial response to chemotherapy based on
platinum is indicated [49]. The objective
of this study is to investigate the therapeutic interventions for adult
individuals diagnosed with advanced ovarian cancer that is linked with
detrimental BRCA mutations, whether inherited or acquired, and who have
previously had at least two rounds of chemotherapy. The focus of this study is
on the management of adult individuals diagnosed with advanced ovarian cancer
that is accompanied with detrimental BRCA mutations, whether inherited or
acquired, and who have previously undergone one or more rounds of chemotherapy.
The objective of this study is to examine the therapeutic interventions for
adult individuals diagnosed with advanced ovarian cancer that is associated with
detrimental BRCA mutation, either in the germline or somatic cells. Furthermore,
this investigation aims to focus on patients who have previously undergone one
or more rounds of chemotherapy. This indication is primarily intended for
individuals who have seen disease progression at least six months following
their most recent administration of platinum-based chemotherapy. Rubraca has
exhibited substantial clinical advantages in these particular cohorts of
patients, hence resulting in its authorization as a targeted therapeutic
approach for ovarian cancer and specific forms of prostate cancer characterized
by BRCA mutations. Like all medications, Rubraca has potential side effects and
should be closely monitored by a skilled healthcare professional. Individuals
who are contemplating the use of Rubraca as a treatment option should engage in
a comprehensive discussion with their oncologist regarding the potential
advantages and disadvantages associated with this medication. This dialogue will
aid in the identification of the optimal treatment strategy tailored to their
unique medical circumstances.
These medications are commonly provided to individuals who possess BRCA
mutations, and in certain instances, to those exhibiting defects in other DNA
repair pathways. Furthermore, current investigations are being conducted to
examine the potential of PARP inhibitors in conjunction with other therapeutic
modalities, including chemotherapy or immunotherapy, with the aim of augmenting
their effectiveness. It is noteworthy to acknowledge that although PARP
inhibitors have demonstrated substantial advantages in certain instances of
breast cancer, their efficacy may not extend universally to all individuals.
Like all forms of cancer treatment, the formulation of personalized treatment
regimens that take into account the patient's unique genetic profile and
medical history is crucial in order to optimize treatment outcomes. Hence, it is
imperative to seek guidance from a certified oncologist in order to ascertain
the most appropriate treatment strategy for individual patients diagnosed with
breast cancer.
1,2,4-triazoles
A collection of new compounds with 1,2,4-triazole scaffolds that have been
variously substituted with different moieties was taken into consideration. The
polynitrogen-based bioisosteres was used in replace of the cyclic amide
pharmacophore (i.e, triazole-thiones and alkylsulfanyl-triazoles). As a result,
a thorough in-silico process was carried out to examine the putative
binding mode of the derivatives within the catalytic domain of PARP-1. A total
of six hits with high binding affinities were chosen, made, and scaled up for
biological testing. These substances were examined for their capacity to inhibit
the PARP-1 enzyme's activity before being put through a cytotoxicity
test on the MCF-7 cell type. Moreover, wound healing tests were used to evaluate
the inhibition of cell migration and invasion [50].
2,3-Difluorophenyl-Linker-Containing PARP-1 Inhibitors
Studies on Olaparib, the first medication authorised to treat some ovarian
cancers, revealed that the N-substituted piperazine was flexible but the
phthalazine fragment was necessary for PARP-1 inhibition potency [9]. Olaparib was discovered to have
inferior antitumor efficacy as other PARP inhibitors rose to prominence [51]. A novel 2,3-difluorophenyl-linker
analogue was created and fluorine was added to Olaparib's phenyl linker
at position 3 in an effort to increase its antitumor effectiveness. In contrast
to Olaparib, molecular docking analysis revealed that Tyr889 and both the
3-position and 2-position fluorine atoms of the analogue made a hydrogen bond.
In order to investigate the structure-activity relationship (SAR) of the
2,3-difluorophenyl-linker analogues of Olaparib, a novel series of
2,3-difluorophenyl-linker analogues derived from Olaparib was designed. It was
then thoroughly evaluated to determine if the type of substituent at the
terminal nitrogen of the piperazine would enhance pharmacological activity.
Finally, a highly potent PARP-1 enzymatic inhibitor
2-(4-(2,3-Difluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pipe-razin-1-yl)nicotine
nitrile with excellent in vitro and in vivo antitumor efficacy against both
BRCA1- and BRCA2-deficient tumour cells, good specificity for BRCA-deficient
cells and a good safety profile was identified as a unique candidate compound
for the development of antitumor drug [50].
Apigenin-Piperazine Hybrid
It has been claimed that Amentoflavone (AMF) is a specific PARP-1 inhibitor that
to AMF has undergone structural changes and trimming resulting in a number of
AMF variants and apigenin-piperazine/piperidine hybrids. One of these
compounds had a strong inhibitory impact on PARP-1 (IC50 =
14.7 nM) and was highly selective for PARP-1 over PARP-2 (61.2- fold). The
aforementioned compound immediately bound to the PARP-1 structure, as
demonstrated by molecular dynamics modelling and the cellular thermal shift
assay. Through the inhibition of PARP-1, studies conducted in vitro and in vivo
revealed a powerful chemotherapy sensitising effect against A549 cells and a
selective cytotoxic effect towards SK-OV-3 cells. additionally showed favourable
safety margins, pharmacokinetic parameters, and acceptable ADME characteristics.
These results showed that this could be a potential lead molecule for
chemosensitizers and the (BRCA-1) deficient cancer therapy [10].
Benzo[de][1]
[7] naphthyridin-7(8H)-ones
As new PARP-1 inhibitors, a group of benzo[de][1]
[7] naphthyridin-7(8H)-ones
with a functionalized long-chain appendage have been developed. The original
attempt resulted in the first-generation PARP-1 inhibitors, which had a terminal
phthalazin-1(2H)-one framework and remarkably high PARP-1 inhibitory activity
(0.31 nM), but only moderate cell potency. Further research led to the
development of the second-generation lead compound, which exhibits strong
potency against the PARP-1 enzyme and BRCA-deficient cells (CC50 0.26
nM), particularly for the BRCA1-deficient MDA-MB-436 cells. The new PARP-1
inhibitors substantially reduced H2O2-triggered PARylation
in SKOV3 cells, increased the accumulation of DNA double-strand breaks within
the cell, and inhibited cell-cycle progression in BRCA2-deficient cells,
according to mechanistic investigations. Additionally, a sizable potentiation of
temozolomide's cytotoxicity was seen. the distinctive structural
features and extraordinarily high potency and stood as a promising drug
candidate [14].
4-(3-(2-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido-[3,4-d]
pyrimidine-7-carbonyl)-4-fluorobenzyl) phthalazin-1(2H)
One comes out as the most promising candidate, with pIC50 values
higher than 8 and strong inhibitory activities against both PARP-1/2 and
PI3K. 4-(3-(2-(6-Amino-4-(trifluoromethyl)pyridin-3-yl) is a compound.
-4-morpholino-5,6,7,8-tetrahydropyrido-[3,4-d]
pyrimidine-7-carbonyl)-4-fluorobenzyl) In cellular assays, phthalazin-1(2H)-one
showed better antiproliferative profiles against cancer cells that were
BRCA-deficient and BRCA-proficient. Comprehensive biochemical and cellular
mechanistic studies have shed light on the clear synergistic effects caused by
the simultaneous suppression of the two targets. In the MDA-MB-468 xenograft
model, demonstrated more effective antitumor activity than the equivalent drug
combination (Olaparib + BKM120), with a tumour growth inhibitory rate of
73.4% and no detectable toxic effects. According to all of the findings,
is a first-generation dual PARP/PI3K inhibitor that is an extremely
potent anticancer drug [16].
5-fluoro-1H-benzimidazole-4-carboxamide derivatives
Novel 5-fluorine-benzimidazole-4-carboxamide analogues were created and produced
in a number of different ways. The ability of each specific substance to inhibit
PARP-1 was tested. To assess the potentiation impact of cytotoxic agents against
cancer cell lines, compounds with strong intrinsic PARP-1 inhibitory potency
have been tested in vitro. These endeavours resulted in the discovery of the
compound, which showed potentiation of temozolomide cytotoxicity in cancer cell
line A549 (PF50 = 1.6), excellent cell inhibitory activity in
HCT116 cells (IC50 = 7.4 nM), and strong inhibition against
the PARP-1 enzyme with an IC50 of 43. nM [52].
3-Oxo-2,3-dihydrobenzofuran-7-carboxamide
Optimization of ((Z)-2-benzylidene-3-oxo-2,3-dihydrobenzofuran-7-carboxamide,
PARP-1 led to a tetrazolyl analogue (IC50 = 35 nM) with
improved inhibition. A promising new lead was produced by isosterically
replacing the tetrazole ring with a carboxyl group (IC50 = 68
nM). This lead was later optimised to produce analogues with strong PARP-1
IC50 values (4–197 nM). The majority of compounds are
selective towards PARP-2 and have IC50 values that are similar to
those of clinical inhibitors, according to PARP enzyme profiling. The mechanism
of interaction with analogue appendages extending towards the PARP-1
adenosine-binding pocket was shown by X-ray crystal structures of the key
inhibitors bound to PARP-1. Breast cancer gene 1 (BRCA1)-deficient cells were
specifically killed by compound
(Z)-3-Oxo-2-(4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1]
[2]
[4]-triazolo[4,3-a]
pyrazine-7-carbonyl)benzylide ne)-2,3-dihydrobenzofuran-7-carboxamide, an
isoform-selective PARP-1/-2 (IC50 = 30 nM/2
nM) inhibitor, in contrast to isogenic BRCA1-proficient cells [19].
Substituted 2-phenyl-2H-indazole-7-carboxamides
A series of potent substituted 2-phenyl-2H-indazole-7-carboxamides were developed
and evaluated as poly (ADP-ribose) polymerase inhibitors (PARP). The result of
this thorough SAR investigation was the discovery of the substituted
5-fluoro-2-phenyl-2H-indazole-7 carboxamide analogue, which demonstrated
excellent PARP enzyme inhibition with IC50 = 4 nM, inhibited
proliferation of cancer cell lines lacking BRCA-1 with CC50 =
42 nM, and demonstrated encouraging pharmacokinetic properties in rats compared
to other lead [53]. The details of
structures and IC50 values of compounds were presented in [Table 2].
Table 2 Synthetic derivatives with their structures and
IC50 values
|
S. No
|
Name of the compounds
|
Structure
|
IC50
|
Ref
|
|
1,2,4-triazoles
|
|
1
|
5-(1H-indol-2-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol
|
|
517.98 nm
|
28
|
|
2
|
3-(All-1-ylsulfanyl)-5-((1-all-1-yl)-indol-2-yl)-4-phenyl1,2,4-triazole
|
|
665.42 nm
|
28
|
|
2,3-Difluorophenyl-Linker analogues
|
|
3
|
2-(4-(2,3-Difluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoyl)pipe
-razin-1-yl)nicotinonitrile
|
|
1.3±0.3 nm
|
29
|
|
Apigenin−Piperazine Hybrid
|
|
4
|
5,7-dihydroxy-2-(4-hydroxyphenyl)-8-((4-thiophene-2-ylmethyl)piperzin-1-yl)methyl)-4H-chromen-4-one
|
|
14.7 nm
|
30
|
|
Benzo[de] [1]
[7]
naphthyridin-7(8H)-ones
|
|
5
|
4-(3-(2-(6-Amino-4-(trifluoromethyl)pyridin-3-yl)-4-morpholino-5,6,7,8-tetrahydropyrido-[3,4-d]pyrimidine-7-carbonyl)-4-fluorobenzyl)phthalazin-1(2H)-one
|
|
3.46 nm
|
31
|
|
3-Oxo-2,3-dihydrobenzofuran-7-carboxamide
|
|
6
|
(Z)-3-Oxo-2-(4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1]
[2]
[4]-
triazolo[4,3-a]pyrazine-7-carbonyl)benzylidene)-2,3
dihydrobenzofuran-7-carboxamide
|
|
30 nm
|
34
|
|
2-Phenyl-2H-indazole-7-carboxamides
|
|
7
|
2-(4-(azetidine-3-carboxamido)-3-fluorophenyl)-5-fluoro-2H-indazole-7-carboxamide
|
|
04 nm
|
35
|
PARP-1 and pathological disorders
PARP-1 is an essential nuclear enzyme that assumes a pivotal function in multiple
cellular activities, principally encompassing DNA repair mechanisms and the
preservation of genomic stability. The aforementioned entity belongs to the PARP
gene family, comprising a collection of enzymes that facilitate the transfer of
ADP-ribose units from nicotinamide adenine dinucleotide (NAD+) to
certain proteins, including the enzymes themselves. Poly(ADP-ribosyl)ation, a
biochemical process, plays a crucial role in the regulation of diverse cellular
activities. DNA damage can arise from a multitude of factors, encompassing
exposure to radiation, chemical agents, and oxidative stress. The activation of
PARP-1 occurs in response to the occurrence of DNA strand breaks, whereby its
primary function is to attract DNA repair proteins to the specific areas of
damage, so aiding in the facilitation of the repair process. PARP-1 plays a
crucial role in preserving the stability of the genome and mitigating the
potential for the development of pathological conditions, such as cancer and
other disorders, by facilitating the repair of DNA damage and preventing the
accumulation of mutations. Nevertheless, although PARP-1 plays a critical role
in the process of DNA repair, excessive activation of this enzyme can lead to
disastrous outcomes. In instances of significant DNA damage, the overactivation
of PARP-1 can result in the depletion of cellular NAD+ and ATP, leading
to an energy deficit and subsequent cell demise. This phenomenon is commonly
referred to as PARP-1 hyperactivation-induced necrosis. This phenomenon holds
significant relevance within specific clinical states and disorders. The
involvement of PARP-1 in pathological illnesses, particularly in cancer therapy,
has been extensively researched, with a specific focus on PARP inhibitors, as
previously indicated. PARP inhibitors have been formulated with the specific
objective of selectively targeting cancer cells that have deficits in DNA repair
mechanisms, such as those harboring BRCA mutations. The function of these
inhibitors involves the obstruction of PARP-1's enzymatic activity,
resulting in synthetic lethality inside cancer cells that possess impaired DNA
repair pathways. However, these inhibitors do not harm normal cells that possess
complete DNA repair processes. In addition to its involvement in cancer, PARP-1
has also been associated with many clinical conditions, such as neurological
diseases. Neurodegenerative disorders, such as Alzheimer's disease and
Parkinson's disease, are characterized by the presence of DNA damage,
oxidative stress, and compromised DNA repair mechanisms. The possible
therapeutic method of inhibiting PARP-1 has been investigated in the context of
countering neurodegeneration and safeguarding neurons against death caused by
DNA damage. In brief, the proper functioning of PARP-1 is crucial for the
preservation of genomic integrity and the repair of DNA lesions. However, the
disruption and excessive activation of PARP-1 have been implicated in the
development of diverse clinical conditions. Conversely, the focused suppression
of PARP-1 in particular pathological scenarios, such as cancer cases
characterized by impaired DNA repair mechanisms, has exhibited encouraging
outcomes as an approach to therapy. Further investigation is required in order
to comprehensively comprehend the intricate functions of PARP-1 in diverse
clinical contexts and to investigate the possible therapeutic advantages of PARP
inhibitors in a range of disorders other than cancer.
PARP-1 and neurodegenerative diseases
Progressive memory loss and motor dysfunction are hallmarks of neurodegenerative
diseases. Among their pathological symptoms are the accumulation of insoluble
proteins in brain deposits, Tau-formed neurofibrillary tangles in the brains of
AD patients, and irreversible neuronal malfunction or death [54]
[55]
[56]. The function of PARP-1
in neurodegenerative disorders has recently been studied. They demonstrated that
-synuclein accumulating in neurons activates PARP-1, and PARylation makes
-synuclein more toxic, accelerating neuronal mortality. Ataxia-telangiectasia
(A-T) mouse and worm models showed elevated amounts of PARylation and markedly
dysfunctional mitochondria. It's interesting to note that PARP-1
reduction reduces A-T neuropathology and enhances neuromuscular performance
[55]
[57]
[58]. As with other
neurodegenerative illnesses like HD, ALS, and multiple sclerosis, excessive
activation of PARP-1 has been linked to these conditions. The signs of disease
can be improved by PARP-1 inhibition [59]
[60]
[61].
PARP-1 and Parkinson’s disease
Another typical neurodegenerative illness, Parkinson's disease primarily
effects the motor system and is frequently associated with cognitive dysfunction
and abnormal behaviour. The loss of dopaminergic (DA) neurons in the substantia
nigra and the development of Lewy bodies, which are closely linked to
mitochondrial dysfunction and α-synuclein aggregation, are two
pathological signs of Parkinson's disease (PD). Recent research suggests
that PARP-1 affects PD development. In line with the notion that aminoacyl-tRNA
synthetase-interacting multifunctional protein 2 (AIMP2)-mediated activation of
PARP-1 is one of the primary causes for the loss of DA neurons, PARP-1
activation is a crucial early event in DA neuronal cell death induced by 6-OHDA
[55]
[62]
[63]
[64]. Lewy bodies contain both AIMP2 and
-synuclein, and AIMP2 can directly interact with and trigger PARP-1. Similar to
this, activated PARP-1 can control a number of pathological PD processes, such
as α-synuclein aggregate formation, mitochondrial dysfunction, and
mitophagy dysregulation [65]
[66]
[67]. Nitric oxide synthase is activated when pathological
α-synuclein (in the shape of an oligomer or an insoluble fibre) is
present. This causes DNA damage and PARP-1 activation. By altering NAD+
stores and energy metabolism, activated PARP-1 affects mitochondrial function.
This is accompanied by depolarization of the mitochondrial membrane potential
brought on by PARylation [57]
[68]. There are many chemicals that are
thought to be sporadic PD pathogenic agents. The standard drug for creating PD
rodent models, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, causes oxidative
stress in old mice, which is followed by the activation of PARP-1 by
Ca2+-dependent enzymes [69].
Additionally, following the silencing of vacuolar protein sorting-associated
protein 35, PARP-1 is increased and inhibition of RNF146 or other pathological
PD alterations. The failure of the intracellular process known as mitophagy,
which removes damaged mitochondria, is linked to Parkinson's disease
(PD). Parkin and PINK1 are both involved in mitophagy, and abnormalities in
PARK6 (PINK1) or PARK2 (parkin) lead to autosomal recessive Parkinson's
disease (PR) [64]
[70]
[71]
[72]
[73]. Research revealed that by blocking
SRIT1, PARP-1 may be involved in mitophagy. Despite being more commonly
associated with the nucleus, PARP-1 can also be found in the mitochondria, where
it PARylates proteins in the electron transport chain and is involved in the
repair of mitochondrial DNA. Similar to nuclear PARP-1, overactivation of
mitochondrial PARP-1 (mtPARP-1) prevents mitochondrial biogenesis, which results
in the demise of neuronal cells [74]
[75]
[76]. Neuroinflammation, dysregulated autophagy, and irregular sleep
patterns are additional PARP-1-related causes of PD. Both the migration of high
mobility group box 1 and the regulation of NF-B transcriptional activity are
ways that PARP-1 causes the neuroinflammation of PD (HMGB1). Particularly,
engaged PARP-1 inhibits SIRT1 and increases HMGB1's acetylation, which
promotes HMGB1 release from cells. HMGB1 can act in the extracellular milieu in
a proinflammatory cytokine-like way, activating microglia, compromising BBB, and
encouraging the expression of inflammatory cytokines, all of which contribute to
the onset of Parkinson's disease (PD). Importantly, PD in rodents has
been treated with an anti-HMGB1 monoclonal antibody. This therapy was able to
significantly reduce oxidative stress, keep DA neurons in the substantia nigra,
and enhance mouse motor performance [64]
[77]
[78]
[79]. Therefore, inhibiting PARP-1 may be a useful strategy for the
therapy of Parkinson's disease [55]. As was already stated, autophagy is essential for maintaining
the brain's regular function. Toxic clumps can be removed by upregulated
autophagy, which is also helpful for reducing inflammation in conditions
affecting the central nervous system. In PD, impaired autophagy can add to the
build-up of -synuclein, which may cause DA neurons to degenerate. Similar to
this, activated PARP-1 speeds up -synuclein aggregation and increases its
neurotoxicity in primary rodent cortical neurons. It has been demonstrated that
excessive PARP-1 activation causes autophagy dysfunction by triggering the mTOR
pathways and PARylating transcription factor EB, which inhibits the
transcription of genes linked to autophagy like LC3-II. In particular, PARP-1
reduction can boost autophagy activity, causing -synuclein to break down [55]
[64]
[80]
[81].
PARP-1 and Alzheimer's disease
Short-term memory loss is an early sign of Alzheimer's disease (AD), the
most prevalent neurological illness. Growing data suggests that tau tangles,
Aβ plaque deposition, and hippocampal neuronal loss are typical
neuropathologies of AD [82]
[83]
[84]. It has been demonstrated that in the brains of AD patients,
PARP-1/PAR co-localizes with A, Tau, and microtubule-associated protein
2 (a branching marker). With the production of reactive oxygen species (ROS)
and/or reactive nitrogen species (RNS), AD and A both boost PARP-1
activity. A deposition by activated PARP-1 can exacerbate AD symptoms; as a
result, PARP-1 can be triggered both before and after Aβ. Excessive
PARP-1 activation was viewed as an important and early change in the
pathogenesis of AD [85]
[86]
[87]
[88]. However, reduced
nucleolar PARP-1 activated DNA cytosine-5-methyltransferase 1 and suppressed
rDNA, serving as an early indicator of cognitive decline in AD. Although the
research concentrated on nucleolar PARP-1 in hippocampal pyramidal cells, it was
found that AD patients complete brains, especially the frontal and temporal
lobes, expressed PARP-1 [89]
[90]. It is believed that persistent
neuroinflammation speeds up the development of neurodegeneration in AD.
According to some reports, the NF-kB subunit RelA can induce neuroinflammation
through PARylation. When there is AD pathology present, activated PARP-1
encourages NF-kB to attach to DNA in microglia. Parallel to this, a number of
studies have shown that inhibiting PARP-1 can halt the development of AD [91]
[92]
[93]
[94]. In mice lacking PARP-1,
Aβ-induced microglial activation is reduced. In the AD rodent model,
treatment with PJ34 (a PARP-1 inhibitor) may reduce microglial activation and
neurodegeneration. Overall, PARP-1 is essential for the inflammatory process
connected to AD [95]
[96]. In numerous AD models, SIRT1 functions
as a neuroprotective component. It controls the progression of AD by preventing
the build-up of A and reducing cognitive loss brought on by ageing [97]
[98]. Notably, after the addition of NAD+ and SIRT1 agonists,
a sizable decrease in DNA damage in AD was seen. In AD, PARP-1 and SIRT1 contend
with one another for a limited supply of NAD+ [99]
[100]
[101]. Previous research
has demonstrated that BBB leaking occurs in the early stages of AD and may be a
factor in dementia and cognitive decline [102]. The BBB's permeability increased as a result of A
deposition in the walls of arterioles and capillaries, which was verified by
autopsy on the brains of AD patients. In this way, PARP-1 is involved in
preserving the structure of the BBB [103].
That is, by encouraging the expression of tight junction proteins, inhibition of
PARP-1 improves barrier stability. Furthermore, the suppression of PARP-1
reduces the endothelial dysfunction brought on by neuroinflammation, indicating
that inhibiting PARP-1 may lessen cognitive impairment by preserving the
integrity of the BBB (88). All of these data point to a critical function for
PARP-1 in the development of AD [55].
PARP-1 in diabetes mellitus
Pancreatic beta cell death causes type 1 diabetes, also known as
insulin-dependent diabetes mellitus, an autoimmune disease [104]. The role of PARP activation in the
process of cell death has been the topic of in-depth research for the past 20
years. Cell toxins, streptozotocin, and alloxan-induced release of various
inflammatory cell mediators like cytokines and free radicals all functionally
inhibit and eventually destroy islets of Langerhans isolated from rats, mice, or
humans. Numerous investigations have looked into the function of PARP in these
processes using different pharmacological enzyme inhibitors. Streptozotocin
application induces DNA strand breaks and PARP activation in separated mouse and
rat islets, a reduction in NAD+ and proinsulin content, and an
inhibition of insulin secretion [105]
[106]
[107]. The beta cell degeneration was prevented by the PARP inhibitors
3-aminobenzamide, nicotinamide, INH2BP, PJ34, and piclonamide because they
reduced beta cell NAD+ levels and attenuated hyperglycemia [108]
[109]
[110]. The effects of PARP
inhibition on complications brought on by diabetes have also been examined. PARP
inhibitors like INO-1001 and PJ34 have been investigated for their effects on
the progression of diabetic nephropathy in Lepr(db/db) (BKsJ) mice, an
experimental model of type 2 diabetes [111]. Both medications reduced diabetes-related albumin excretion and
mesangial expansion as well as prevented hyperglycemia. Additionally, PJ34 has
been shown to be efficacious when administered orally to rats with a rat model
of early diabetic neuropathy [112].
Evidence suggests that streptozotocin-induced diabetes in rodents reverses
neurological and neurovascular deficits when nicotinamide, a weak PARP
inhibitor, is administered.
PARP-1 in HIV infection
A critical stage in the life cycle of HIV-1 and other retroviruses is the
integration of a DNA duplicate of the viral genome. Growing evidence points to
PARP's participation in HIV infection because PARP is necessary for
nicking host cell DNA in order for HIV-1 virus DNA to be incorporated [113]. Although the virally encoded
integrase is essential for this process, it is also thought that uncharacterized
cellular factors play a role in its conclusion. According to reports, DNA damage
sensors like PARP-1 are crucial for promoting HIV integration [114]
[115]. Independent investigations revealed that nicotinamide,
trisubstituted benzamides, and benzopyrone derivatives have strong antiviral
effects [116]
[117]. Similar findings were also reported
by studies that employed chemical, antisense, and dominant negative inhibition
as three distinct PARP inhibitory strategies [118].
PARP-1 and Ageing
The phenomenon of ageing is the gradual loss of the body's physical and
psychic capacity for environmental adaptation. Recent research showed that the
A-T mutated (ATM)-disrupted mice, which was used as an animal model of A-T, age
more quickly when PARP-1 is overactive due to DNA damage and chronic
neuroinflammation [119]. In accordance
with this discovery, PARP-1 inhibitors can enhance senescent cells functionality
by raising NAD+ levels and SIRT1 activity. In fact, SIRT1 and
NAD+ supplementation through therapy with nicotinamide mononucleotide or
nicotinamide riboside, both of which are NAD+ precursors, have
anti-aging effects [120]
[121]
[122]
[123].
Clinical, Pre-clinical Studies of PARP inhibitor
PARP-1 inhibitors have undergone comprehensive investigation in both pre-clinical
settings, encompassing laboratory and animal investigations, as well as clinical
trials involving human participants. The safety, efficacy, and potential
applications of PARP-1 inhibitors in many disorders, especially cancer, have
been assessed in this research. During the pre-clinical phase, laboratory
experiments and animal models were employed to investigate the mechanisms of
action, toxicity profiles, and possible therapeutic effects of PARP-1
inhibitors. The primary objective of these research was to prove the proof of
concept and offer significant insights into the drug's efficacy against
particular forms of cancer, particularly those characterized by defects in DNA
repair mechanisms. Preclinical investigations were conducted to assess the
anticancer efficacy of PARP-1 inhibitors in cancer cell lines and xenograft
models obtained from patient malignancies. These researches have contributed to
the identification of malignancies characterized by unique DNA repair pathway
abnormalities, which exhibit heightened sensitivity to PARP inhibition. The
study involved the implementation of experimental procedures by researchers in
order to gain insights into the mechanisms via which PARP-1 inhibitors impede
DNA repair processes and trigger synthetic lethality in cancer cells harboring
BRCA mutations or other abnormalities in DNA repair mechanisms. Preclinical
experiments have also examined the potential of synergizing PARP-1 inhibitors
with other cancer treatments, such as chemotherapy or radiation therapy, in
order to augment therapeutic effects. Animal toxicology studies were undertaken
to assess the safety of PARP-1 inhibitors, ascertain potential adverse effects,
and establish suitable dosages for forthcoming clinical trials. The evaluation
of safety and efficacy of PARP-1 inhibitors in human patients is carried out
through a series of sequential steps in clinical studies. The studies encompass
individuals who have been diagnosed with specific forms of cancer, specifically
those who possess BRCA mutations or other impairments in the DNA repair pathway.
Phase I trials typically comprise a limited cohort of patients and primarily aim
to ascertain the appropriate dosage range of the PARP-1 inhibitor, comprehend
its pharmacokinetic profile (i. e., absorption, distribution,
metabolism, and excretion within the body), and detect any potential adverse
effects. Phase II trials aim to augment the patient cohort and conduct more
comprehensive investigations into the efficacy of the medication in distinct
cancer subtypes. The researchers seek to identify indications of tumor reduction
or stability and evaluate the drug's general safety and tolerability.
Phase III trials are extensive, randomized investigations that aim to compare
the efficacy of the PARP-1 inhibitor with standard treatments or a placebo
within well-defined patient populations. The primary objective of these trials
is to conclusively show the drug's effectiveness, safety, and possible
advantages for patients. If the PARP-1 inhibitor exhibits substantial
therapeutic advantages and establishes safety in Phase III trials, it may be
eligible for regulatory approval for particular purposes. Post-marketing studies
are ongoing to assess the extended safety and efficacy of the medicine in a more
diverse patient cohort. In brief, extensive pre-clinical and clinical
assessments have been conducted on PARP-1 inhibitors to comprehensively
investigate their mechanisms of action, safety characteristics, and therapeutic
efficacy, with a specific focus on their application in the field of cancer
therapy. The aforementioned investigations have resulted in the authorization of
PARP-1 inhibitors for particular cancer indications and continue to propel
on-going research endeavours aimed at investigating their potential applications
in other medical conditions.
