Degradation of Cyclin-Dependent Kinase: A New Weapon for Cancer Therapy

Abstract

Targeting cyclin-dependent kinase (CDK) families is a promising strategy for cancer therapy due to the close association between CDKs and an abnormal cell cycle or transcriptional regulation. However, after extensive clinical use, small molecule inhibitors of CDKs have also exposed issues, such as off-target effects or acquired drug resistance. Targeting protein degradation technology, which has been validated to be effective for many targets, has undergone more than 20 years of development, and some of these methods have been pushed into clinical trials. In this review, we summarized some successful reports on CDK-targeted degradation during recent years. Moreover, some challenging issues and future development trends are highlighted in the prospect section, which might provide updated insight into the development of novel CDK-targeted degraders with great potential as a new weapon for cancer therapy.

Keywords

CDK - degradation - cancer - therapy

Introduction

The concept of the cell cycle and regulatory restriction points was first mentioned in the 1970s and early 1980s. In 2001, researchers behind the core work of identifying cyclin-dependent kinases (CDKs) and their partner cyclins in the cell cycle process were awarded the Nobel Prize.[1] [2] In recent years, with the continuous deepening of related research, dysregulation of cell growth and division has been proven to play a crucial role in the occurrence and development of cancers.[3] [4] [5] [6] Moreover, our understanding of how specific CDKs regulate transcription and maintain the oncogenic state has advanced considerably.[7] [8] [9] [10] Thus, CDK families have continuously become important targets for cancer treatment, which has led to considerable efforts to develop CDK inhibitors as cancer therapeutics. CDKs are Ser/Thr kinases that catalyze the phosphorylation of corresponding downstream proteins during the cell cycle and transcriptional regulation and usually combine with endogenous cyclin proteins to form a catalytic conformation. According to their different functions, CDKs can be divided into two main categories ([Fig. 1A]): cell cycle-associated CDKs (CDK1, CDK2, CDK4, and CDK6) and transcription-associated CDKs (CDK7, CDK8, CDK9, CDK12, CDK13, and CDK19).[11] [12] [13] [14]

Fig. 1 (A) Comparison of CDKs with different functions. (B) Approved CDK4/6 inhibitors. CDK, cyclin-dependent kinase.

CDKs orchestrate oncogenic transformation through at least three interconnected mechanisms. First, mitogenic CDK4/6-cyclin D signaling initiates retinoblastoma (Rb) protein phosphorylation, liberating E2F factors to drive unscheduled G1–S transition and propagate chromosomal instability. Subsequent CDK2 and CDK1 activity enforces DNA re-replication and mitotic bypass, further amplifying genomic heterogeneity. Second, transcriptional CDK (notably CDK7, CDK9, and CDK12/13) govern RNA polymerase II pause release and productive elongation. This dependency sustains the expression of short-lived oncogenic transcripts (e.g., anti-apoptotic and growth factors), rendering tumors highly vulnerable to disruption of C-terminal domain (CTD) phosphorylation. Third, CDKs modulate processes such as DNA damage checkpoints, splicing, and translation, creating context-specific vulnerabilities. For example, CDK12 loss truncates homologous repair transcripts and induces PARP inhibitor sensitivity, whereas CDK9 inhibition preferentially depletes MCL-1 and intracisternal A-particle (IAP) mRNAs, promoting mitochondrial apoptosis. Together, these pleiotropic yet druggable functions establish CDKs as central executors of proliferative, transcriptional, and therapeutic liabilities in cancer.[15]

To date, the development of small molecule inhibitors of the CDK family has always been a popular research topic for scholars in the field of biological health. Starting from the first clinical CDK inhibitor, flavopiridol,[16] an increasing number of small molecule CDK inhibitors targeting different CDK subtypes are entering clinical research.[17] [18] [19] [20] [21] Among them, the CDK4/6 inhibitors palbociclib (from Pfizer), ribociclib (from Novartis), abemaciclib (from Lilly), dalpiciclib (from Jiangsu Hengrui), and trilaciclib (from G1 Therapeutics) were successively approved ([Fig. 1B]).[22] [23] [24] [25] [26] [27] However, with the widespread use of CDK inhibitors for clinical indications, some clinically observable issues and needs have also emerged, including side effects caused by poor CDK isoform selectivity, a lack of understanding of the precise mechanism of action, and hence, the absence of appropriate biomarkers and reduced tolerance caused by activation of other compensatory pathways.[28] [29] [30] [31] Briefly, the understanding and development of CDKs and the related drugs still require in-depth research.

The earliest research on targeting protein degradation (TPD) can be traced back to 2001. Sakamoto et al reported the peptide-based proteolysis targeting chimera (PROTAC) for the targeted degradation of methylthioamide peptidase 2 (METAP2), an enzyme known to effectively inhibit angiogenesis.[32] After more than two decades of development, significant breakthroughs have been made in TPD technology.[33] [34] [35] [36] Moreover, many TPD agents with different targets have successively entered clinical studies related to cancer treatment. The representative degradation agent Vepdegestrant (ARV-471), developed by Arvinas and Pfizer, entered phase III clinical trials.[37] [38] [39] [40] [41] The development and maturity of this technology also demonstrated breakthroughs and improvements in cancer therapeutic schedules. In this work, we reviewed recent research on the proteasome degradation of different CDK isoforms (2017–2025), which has focused mainly on PROTACs, molecular glues, and hydrophobic tag-based degraders. We aimed to analyze the feasibility of applying TPD technology to CDKs and to provide insights for future research.

Progress of PROTAC on Various Cyclin-Dependent Kinase Isoforms

PROTACs are heterobifunctional molecules composed of three modules: a target protein (protein of interest [POI]) ligand, an E3 ubiquitin ligase ligand, and a connecting linker. Their mechanism of action involves the simultaneous binding of the POI and an E3 ligase to form a POI–PROTAC–E3 ternary complex. This event recruits the E3 ligase to ubiquitinate the POI, marking it for recognition and degradation by the 26S proteasome. The PROTAC molecule is subsequently released and can catalyze multiple rounds of degradation. This strategy does not require occupancy of the target's active site, enabling the elimination of scaffold or structural proteins. Key advantages include their catalytic nature, potential to overcome drug resistance, and the ability to target undruggable proteins, positioning PROTACs as one of the most promising platforms for clinical translation in the field of targeted protein degradation.[35]

PROTACs of CDK2

CDK2, which is activated by the binding of cyclin E1, cyclin E2, and cyclin A2, is a core cell cycle regulator that is active in the G1 phase and throughout the S phase in dividing cells.[42] [43] [44] [45] Based on incomplete statistics, research describing the use of PROTAC degraders on CDK2 has been published. In 2021, Wang et al reported a first-in-class CDK2 selective degrader named CPS2 (1, [Fig. 2]) for acute myeloid leukemia (AML) differentiation therapy. In the construction of CPS2, J2 (a derivative of the CDK2 binder JNJ-7706621) and lenalidomide (a binder of CRBN) were chosen and linked by click chemistry.[46] CPS2 significantly inhibited CDK2 in AML cell lines (NB4, U937, and HL60) in a dose-dependent manner; however, the levels of CDK1, 4, 6, and 9 remained relatively unaffected, indicating good degradation selectivity of the degrader. Moreover, CPS2 markedly induced the differentiation of AML cell lines and primary patient cells, suggesting the potential of CPS2 for AML therapy and CDK2-related biomedical studies. In the same year, Hati et al identified PROTAC-8 (2, [Fig. 2B]), an AZD5438-based VHL-recruiting PROTAC that protects against cisplatin-induced ototoxicity and hearing loss, which created new opportunities for the application of PROTACs in cancer treatment and prognosis.[47] In 2025, Kwiatkowski's group reported compound 3 ([Fig. 3]),[48] an orally bioavailable and highly selective CDK2-targeting PROTAC discovered through structure-guided design. Compared with a clinical-stage CDK2 inhibitor, this degrader demonstrated superior phenotypic selectivity by preferentially eliminating CCNE1-amplified cancer cells while sparing nonamplified counterparts. In HCC169 xenograft models, a single dose sustained >90% CDK2 degradation and Rb phosphorylation inhibition, leading to durable tumor regression. In the same year, Kwiatkowski et al developed a highly selective CDK2 degrader, Cpd1 (4, [Fig. 3]), which unexpectedly also mediated the degradation of cyclin E1. Owing to its enhanced potency and selectivity for CDK2, this degrader drove antiproliferative activity with greater specificity against CCNE1-amplified cancer cells than small molecule inhibitors. Furthermore, the concurrent depletion of CDK2 and cyclin E1 resensitized palbociclib-adapted breast cancer cells to cell cycle arrest.[49]

Fig. 2 Development of CDK2 PROTAC 1 (A) and 2 (B). CDK, cyclin-dependent kinase; PROTAC, proteolysis targeting chimera.

Fig. 3 Structures of selective CDK2 PROTACs 3 and 4. CDK, cyclin-dependent kinase; PROTAC, proteolysis targeting chimera.

PROTACs of CDK4/6

CDK4 and CDK6 (CDK4/6) are critical mediators of the cellular transition to S phase and are important for the initiation, growth, and survival of many cancer types. The best-documented function of CDK4/6-cyclin D in driving cell proliferation is the phosphorylation of the Rb protein, which leads to the release of E2Fs and the upregulation of E2F transcriptional targets.[50] [51] [52] [53] In 2019, the first PROTACs for CDK4/6 were obtained from palbociclib and ribociclib by Zhao and Burgess, which were named pal-pom (5, [Fig. 4]) and rib-pom (6, [Fig. 4]), respectively.[54] In the degradation ability test, palbociclib-based CRBN-recruiting PROTAC (5) showed better degradation of CDK4/6 than rib-pom (6) due to better kinase binding affinity, with DC₅₀ values of 12.9 ± 3.5 nmol/L for CDK4 and 34.1 ± 7.3 nmol/L for CDK6 in the MDA-MB-231 cell line. Moreover, mechanistic research indicated that the CDK4/6-Rb-E2F axis was also downregulated due to the degradation of CDK4/6. Palbociclib-based PROTACs have been widely used for research on CDK4/6-related degradation or codegradation of other proteins. As shown in [Fig. 5], PROTAC 6 (7, [Fig. 5]),[55] BSJ-02-162 (8, [Fig. 5]),[56] CP-10 (9, [Fig. 5]),[57] and YX-2-107 (10, [Fig. 5])[58] were developed as palbociclib-based CRBN-recruiting PROTACs with various linkers by four different groups. Interestingly, PROTAC 6 (7, [Fig. 5]), CP-10 (9, [Fig. 5]), and YX-2-107 (10, [Fig. 5]) preferentially degraded CDK6 in the tested cell lines, with the DC₅₀ values of 2.1 nmol/L (9 in the U251 cell line) and 4.4 nmol/L (10 in the BV173 cell line). Notably, in the research of CP-10 (9, [Fig. 5]), mutated and overexpressed CDK6 could still be degraded by CP-10, which might provide a new method for the treatment of mutant drug-resistant cancer. BSJ-02-162 (8, [Fig. 5]) was identified as a CDK4/6 dual-target degrader. Moreover, the results of quantitative proteomics showed that IKZF1/3 were also degraded synchronously. The authors believe that simultaneously degrading CDK4/6 and IKZF1/3 has an enhanced antiproliferative effect on MCL cell lines compared with that of palbociclib, lenalidomide, or a selective CDK4/6 degrader. Another thought-provoking aspect is that similar degradation agents might have varying abilities to degrade proteins in different cells, which is a future research direction. In 2025, He et al reported the rational design of a potent CDK4/6 protein degrader, compound 11 ([Fig. 5]). This compound achieved dual degradation of CDK4 and CDK6 proteins with DC₅₀ values of 10.5 and 2.5 nmol/L, respectively. It also exhibited antiproliferative activity against Jurkat cells (IC₅₀ = 0.18 μmol/L) and induced dose-dependent apoptosis and G1 phase cell cycle arrest.[59]

Fig. 4 Structures of pal-pom (5) and rib-pom (6).

Fig. 5 Structures of Palbociclib and its analogue based CDK4/6 PROTAC 7–16. CDK, cyclin-dependent kinase; PROTAC, proteolysis targeting chimera.

In addition to CRBN-recruiting PROTAC, several other E3 ubiquitin ligases and their ligands have also been reported for studying the degradation mechanism of CDK4/6. Anderson et al reported a palbociclib-based IAP-recruiting PROTAC (12, [Fig. 5]). Similar to compounds 7–9 mentioned above, 12 showed better degradation of CDK6 than of CDK4 in cells. However, this type of PROTAC might increase the sensitivity of cells that require IAPs for survival.[60] Moreover, Steinebach et al developed a novel selective CDK6 degrader (13, [Fig. 5]) based on palbociclib and a VHL ligand, which showed potent and long-lasting degradation in human and mouse cells and inhibited the proliferation of several leukemia, myeloma, and breast cancer cell lines.[61] Compared with that of 12, VHL-recruiting PROTAC 13 exhibited a better broad-spectrum degradation effect. In 2023, Pu et al reported a PROTAC degrader probe (14, [Fig. 5]) for CDK4/6 based on DCAF16 (DDB1- and CUL4-associated factor 16, mainly distributed in the nucleus), which showed potent inhibitory activity against CDK4/6 and decreased the level of the CDK4/6 protein in MDA-MB-231 cells in a concentration- and time-dependent manner. Moreover, the toxicity of 14 in normal cells was 7 times lower than that of palbociclib, and 14 exhibited therapeutic potential in MDA-MB-231 xenograft models in vivo.[62] This finding also indicates that the subcellular localization of E3 ubiquitin ligases may affect the degradation efficiency of PROTACs.

The codegradation of multiple proteins with a single compound provided the opportunity for collaborative cancer treatment. Verano et al reported the development of ALV-07-082-03 (15, [Fig. 5]), a CDK4/CDK6/Helios triple degrader that consists of palbociclib, which suppressed downstream CDK4/6 signaling and inhibited proliferation of cancer cells as well as enhanced immunomodulatory activity in comparison to the parental CDK4/6 inhibitor palbociclib or the selective Helios degrader DKY709.[63] Similarly, Xiong et al presented a novel PROTAC approach, termed bridged PROTAC, which utilizes a small-molecule binder of the target protein's binding partner to recruit the protein complex into proximity with an E3 ubiquitin ligase to target undruggable proteins. The novel PROTAC MS28 (16, [Fig. 5]) was successfully developed to effectively degrade cyclin D1 with faster degradation kinetics and superior degradation efficiency than CDK4/6 by recruiting the CDK4/6-cyclin D1 complex to the VHL E3 ligase, which provides a new strategy for the degradation of undruggable proteins that do not contain small-molecule binders.[64]

PROTACs of CDK7 and CDK8

CDK7 is a pivotal CDK family member with essential functions in cell cycle progression and transcription. Assembling with cyclin H and MAT1 in the cytoplasm to form the CAK complex, it activates CDKs 1, 2, 4, and 6 via T-loop phosphorylation to propel the cell cycle. Additionally, as part of the TFIIH complex, CDK7 directly contributes to transcriptional regulation.[65] [66] [67] [68] [69] CDK8, which might serve as a new cancer biomarker and is considered to be a potential target for cancer therapeutics, plays a vital role in regulating transcription either through its association with the mediator complex cyclin C or by phosphorylating transcription factors.[70] [71] [72] [73] [74] In 2024, Ji et al reported the first CDK7 degrader, JWZ-5-13 (17, [Fig. 6]), which was constructed by linking an ATP-competitive CDK7 ligand to a CRL2^VHL E3 ligase recruiter. 17 effectively degraded CDK7 in a variety of cancer cell lines and significantly inhibited cell proliferation. Furthermore, it demonstrated favorable bioavailability in a mouse pharmacokinetic study.[75] Hatcher et al reported a novel CRBN-recruiting PROTAC, JH-XI-10-02 (18, [Fig. 6]), based on a derivative of cortistatin A, a natural product isolated from the marine sponge Corticium simplex that was identified as a potent and selective inhibitor of CDK8. Compound 18 significantly inhibited CDK8 in Jurkat cells. However, in CRBN-knockout Molt14 cells, CDK8 degradation was not observed. Although there are few relevant reports, PROTAC strategies targeting CDK8 still have significant development potential and research value.[76]

Fig. 6 Structures of JWZ-5-13 (17) and JH-XI-10-02 (18).

PROTACs of CDK9

CDK9 is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. CDK9 is mainly involved in the synthesis and processing of eukaryotic mRNA. Approximately 80% of CDK9 molecules form heterodimers with Cyclin T1, which is also called positive transcription elongation factor b (p-TEFb) and is required for the phosphorylation of the RNA polymerase II (RNA Pol II) CTD and transcription elongation. The remaining 20% of cells form complexes with Cyclin T2A, Cyclin T2B, or Cyclin K. CDK9 expression is dysregulated in various types of cancer. Inhibition or degradation of CDK9 results in transient transcriptional suppression and preferential depletion of apoptosis-related proteins with short half-lives, such as Mcl-1, c-Myc, and XIAP.[77] [78] [79] [80] Research on the development of CDK9 PROTACs seems to be quite popular, and the types of CDK9-binding ligands are also quite diverse. In 2017, Robb et al reported the first example of a PROTAC (19, [Fig. 7]) based on an aminopyrazole derivative that selectively degrades CDK9 while sparing other CDK family members in HCT116 cells, which resulted in reduced phosphorylation of Ser2 on RNA Pol II and decreased the levels of Mcl-1.[81] In another report, King et al discussed the influence of linker length on the degradation efficiency of an aminopyrazole-based CRBN-recruiting PROTAC. PROTAC 2 (20, [Fig. 7]) was found to selectively degrade CDK9 in MiaPaCa2 cells (DC₅₀ = 158 ± 6 nmol/L) and to sensitize them to Venetoclax-mediated growth inhibition.[82] In 2018, THAL-SNS-032 (21, [Fig. 7]), a selective CRBN-recruiting CDK9 degrader developed from SNS-032, was reported to induce rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, other mechanistic studies have indicated that CDK9 degradation has prolonged cytotoxic effects compared with those of CDK9 inhibition.[83] Similarly, Pei et al reported SNS-032-based PROTAC bearing piperlongumine (PL) moiety (22, [Fig. 7]). In this work, PL was identified as a new covalent E3 ligase ligand of KEAP1, and PROTAC 22 was proven to induce CDK9 degradation in a ubiquitin–proteasome-dependent manner and to have more potent effects than SNS-032 against various tumor cells in vitro, these effects might be the driving force for the development of different types of CDK9 degraders.[84] In recent years, some other classic ligands of CDK9 were used in the construction of CRBN-recruiting PROTACs, including Wogonin (23, [Fig. 8]),[85] BAY-1143572 (24, [Fig. 8]),[86] analogues of LDC3140 (25, [Fig. 8])[87] and AT7519 (26, [Fig. 8]).[88] In 2024, Nie et al reported the design, synthesis, and extensive biological evaluation of a novel orally bioavailable, potent, and selective CDK9 degrader. The developed PROTAC demonstrated desirable potency (DC₅₀ = 3.94 nmol/L) and high efficacy (Dmax = 96%) in degrading CDK9, effectively inhibiting the proliferation of triple-negative breast cancer (TNBC) MDA-MB-231 cells. PROTACs developed based on these ligands exhibited good and selective CDK9 degradation activity in the tested cells. Moreover, successful reports on the development of these CDK9-related PROTACs also provide new feasible solutions for the treatment of CDK9-related cancers.

Fig. 7 Structures of CDK9 PROTAC 19–22. CDK, cyclin-dependent kinase; PROTAC, proteolysis targeting chimera.

Fig. 8 Structures of CDK9 PROTAC 23–26. CDK, cyclin-dependent kinase; PROTAC, proteolysis targeting chimera.

PROTACs of CDK12/13

CDK12/cyclin K is a bifunctional complex implicated in cell division and transcription. Similar to CDK9, the active CDK12/cyclin K complex is recruited to the transcription start site by the polymerase II-associated factor 1 complex before elongation, which plays an indispensable role in the phosphorylation of the CTD of RNA Pol II during elongation.[89] [90] [91] In addition to transcription, CDK12 is also a key regulator of the transition from G1 to S phase, which is a vital step for DNA replication in the cell cycle.[92] [93] Thus, targeting CDK12 may become an ideal strategy for cancer treatment. However, existing CDK12 inhibitors potently inhibit the closest isoform of CDK13, which could cause potential toxicity.[94] [95] Therefore, the degradation of CDK12 or CDK12/13 may be more beneficial than inhibition.

In 2021, Jiang et al reported the first rational design and characterization of a CDK12-specific PROTAC named BSJ-4-116 (27, [Fig. 9]), which could selectively degrade CDK12 and result in premature cleavage and poly(adenylation) of DNA damage response (DDR) genes. Moreover, this work promoted the identification of two specific mutations in the G-loop of CDK12, Ile733Val and Gly739Ser, which might reduce the binding and efficacy of small molecule inhibitors or degradation agents.[96] Subsequently, Niu et al identified a potent CRBN-recruiting PROTAC degrader, PP-C8 (28, [Fig. 9]), based on the noncovalent dual inhibitor of CDK12/13, SR-4835, which showed high degradation selectivity toward CDK12, as well as its partner cyclin K. Importantly, 24-induced CDK12-cyclin K degradation suppresses DDR-related gene expression and shows a substantial synergistic antiproliferative effect with PARP inhibition in TNBC, which might overcome the current PARP inhibitor resistance in cancer treatment.[97] Additionally, in the field of TNBC treatment, Yang et al reported a highly potent and selective dual CDK12/13 PROTAC, compound 29 ([Fig. 10]), with DC₅₀ values of 2.2 nmol/L (for CDK12) and 2.1 nmol/L (for CDK13) in MDA-MB-231 cells, respectively.[98] Moreover, 29 significantly improved the antiproliferative activity and suppressed the expression of DDR genes in a time- and dose-dependent manner in vitro. In 2024, the same research group designed and synthesized a novel CDK12/13 PROTAC degrader ZLC491 (30, [Fig. 10]) by introducing a rigid linker into the structure of 29. In TNBC MDA-MB-231 cells, this compound potently and concertedly degraded both CDK12 and CDK13, with DC₅₀ values of 32 and 28 nmol/L, respectively. Global proteomic analysis and mechanistic studies confirmed that ZLC-491 selectively induces the degradation of CDK12/13 in a cereblom- and proteasome-dependent manner and exhibits an oral bioavailability of 46.8%.[99] That same year, researchers performed subsequent optimization based on 30, finding the orally bioavailable YJ1206 (31, [Fig. 10]) (IC₅₀ = 12.55 nmol/L; oral bioavailability = 59.31%). This compound effectively suppressed the proliferation of prostate cancer cell subpopulations while sparing benign immortalized cells. Intriguingly, both degradation and genetic knockout of CDK12/13 led to activation of the AKT pathway. Combining CDK12/13 targeted degradation with AKT pathway inhibition resulted in a synthetic lethal effect in preclinical prostate cancer models.[100] Therefore, for targets with high homology but different therapeutic functions, synchronous protein degradation strategies may be more applicable than the design of selective small molecule inhibitors.

Fig. 9 Structures of CDK12/13 PROTAC 27 and 28. CDK, cyclin-dependent kinase; PROTAC, proteolysis targeting chimera.

Fig. 10 Structures of CDK12/13 PROTAC 29–31. CDK, cyclin-dependent kinase; PROTAC, proteolysis targeting chimera.

PROTACs of Multiple CDK Isoforms

Due to the high homology of some CDK isoforms, there are numerous difficulties associated with the development of a single inhibitor for a certain CDK subtype.[101] [102] Drawing on the successful experience of designing PROTACs for CDK12/13, the development of PROTACs with multiple CDK isoforms may overcome the shortcomings of a single CDK subtype of degradation agent, including off-target effects or acquired drug resistance.

In 2020, Teng et al developed the CDK2/5 dual degrader TMX-2172 (32, [Fig. 11]). In OVCAR8 cells (CCNE1 high expression), 32 showed significant degradation selectivity for CDK2 and CDK5 over other CDK isoforms, and the antiproliferative activity in OVCAR8 cells depended on CDK2 degradation. On the other hand, 32 may be a useful preliminary chemical tool for investigating CDK5-dependent biology in contexts where CDK2 is unlikely to play a role.[103] In the same year, Zhou et al identified a CDK2/9 dual degrader named F3 (33, [Fig. 11]), which potently induced the degradation of both CDK2 (DC₅₀ = 62 nmol/L) and CDK9 (DC₅₀ = 33 nmol/L) in human prostate cancer PC-3 cells.[104] In another study, Wei et al developed the first orally bioavailable prodrug of PROTAC based on ribociclib (34, [Fig. 11]) for degrading CDK2/4/6 in vivo.[105] The highlight of this work is the use of a prodrug strategy to improve the solubility and bioavailability of PROTACs in vivo while maintaining their strong degradation ability, which suggests that in the PROTAC design process, the drug properties of molecules should be fully considered.

Fig. 11 Structures of PROTAC 32–34 of multi-CDK isoforms. CDK, cyclin-dependent kinase; PROTAC, proteolysis targeting chimera.

Summary of PROTACs

The efficacy data of several representative PROTACs are summarized in [Table 1]. PROTAC degraders offer a unique mechanism of action, enabling the complete elimination of undruggable or drug-resistant proteins and overcoming mutation-driven escape. However, their development faces several challenges, including large molecular size, poor oral bioavailability, limited tissue selectivity, potential resistance risks, and insufficient long-term toxicity assessment. Moving forward, strategies such as artificial intelligence (AI)-assisted optimization of ternary complex kinetics to reduce molecular size, systematic screening of highly expressed E3 ligases to expand the ligand toolbox, and the development of prodrugs or antibody–PROTAC conjugates for improved delivery may help overcome these limitations.

Table 1 Efficacy profiles of representative PROTACs for major cyclin-dependent kinase isoforms

Compd.	CDKS	DC50 (nmol/L)	Dmax (%)	Cell line	IC50 (nmol/L)	F (%)	Protein recruitment
3	CDK2	17	91	MKN1	9	21.0	CRBN
11	CDK4/6	10.5/2.5	100/96	Jurkat	183	15.1	CRBN
17	CDK7	78	95	Jurkat	160	5.2	VHL
18	CDK8	20	100	Jurkat	56	12.6	CRBN
26	CDK9	30	91	MOLM-13	120	12.1	CRBN
31	CDK12/13	32/28	90	MDA-MB-231	620	46.8	CRBN

Abbreviations: PROTAC, proteolysis targeting chimera; CDKs, cyclin-dependent kinases.

Advances in Molecular Glues Targeting CDK Isoforms

Molecular glues are a class of monofunctional small molecules that act by inducing novel, productive interactions between a target protein and an E3 ubiquitin ligase complex. Unlike bifunctional PROTACs, which physically link two proteins, molecular glues often function by binding to a shallow pocket on the E3 ligase or the target, thereby creating a new interfacial surface for recognition and binding. This event leads to the ubiquitination and proteasomal degradation of the target protein, effectively depleting it from the cell.[106] [107] Targeted protein degradation with molecular glue degraders has become a powerful therapeutic modality for eliminating classically undruggable disease-causing proteins through proteasome-mediated degradation.[108] [109] [110] However, the lack of universal molecular glue design principles and strategies limits the efficiency and applicability of molecular glue discovery. Even so, there are still some successful cases of CDK degradation through molecular glue strategies, which might provide some ideas for novel CDK-related molecular glue degraders.

Molecular Glue of CDK4

In 2023, Toriki et al identified a minimal covalent handle (but-2-ene-1,4-dione, fumarate derivative) using ribociclib as a prototype, which could work as a molecular glue (35, [Fig. 12]) to induce the proteasome-mediated degradation of CDK4 in cancer cells. Chemoproteomic profiling revealed interactions between molecular glue 35 and the covalent handle of RNF126 as well as other RING family E3 ligases, providing a novel strategy for converting protein-targeting ligands into covalent molecular glue degraders.[111]

Fig. 12 Structures of molecular glue degrader 35 for CDK4. CDK, cyclin-dependent kinase.

Molecular Glue of CDK12/cyclin K

Compared with the therapeutic effects of PROTACs of CDK12, interference with the binding between CDK12 and its partner cyclin K or induction of cyclin K degradation seems to produce better therapeutic effects. Based on incomplete statistics, at least six articles demonstrated the effectiveness of the strategy. In 2020, Słabicki et al reported CR8 (36, [Fig. 13]), the first molecular glue degrader that depletes cyclin K.[112] The CDK12-binding form of 36 has a solvent-exposed pyridyl moiety that can induce the formation of a complex between CDK12–cyclin K and the CUL4 adaptor protein DDB1, which results in the ubiquitination and degradation of cyclin K and indirect inhibition of the function of CDK12. The binding mode of the DDB1–CDK12–cyclin K ternary complex with 36 is shown in [Fig. 13]. The phenylpyridine moiety of 36 is exposed to the solvent region of CDK12 and binds to the BPC domain of DDB1, which acts as a bridge between the CDK12/cyclin K complex and DDB1.

Fig. 13 Structures of CR8 (36) and binding mode of DDB1–CDK12–Cyclin K ternary complex with 36 (PDB: 6TD3). CDK, cyclin-dependent kinase.

Based on the discovery of the CUL4–RBX1–DDB1 ligase core for the effective degradation of Cyclin K, several molecular glue degraders containing novel DDB1 binding pharmacophores for Cyclin K were developed, including HQ461 (37, [Fig. 14]),[113] NCT02 (38, [Fig. 14]),[114] 39 ([Fig. 14]),[115] SR-4835 (40, [Fig. 14]),[116] and derivatives of AT7519 (41, [Fig. 14]).[117] The successful development of these molecular glue degraders provides new insight for effectively regulating the function of CDKs, which indirectly disrupts the function of CDKs by degrading the related partner cyclins. Compared with PROTACs, molecular glue degraders possess advantages such as small molecular weights, good drug-like properties, low off-target effects, and low synthesis difficulty. However, how to rationally optimize molecular glue degraders is still unclear, and a better understanding of the molecular mechanisms and medicinal chemistry of molecular glue degraders is essential for translating targeted CDK degradation strategies into practical clinical applications.

Fig. 14 Structures of molecular glue degraders 37–41. The red section are potential DDB1 binding pharmacophores, and the blue section is the CDK12 binding moieties. CDK, cyclin-dependent kinase.

Summary of Molecular Glue

Molecular glue degraders offer distinct advantages, including low molecular weight (typically <600 Da), high oral bioavailability, excellent cell membrane permeability, and straightforward synthesis. They function by inducing novel protein–protein interactions between an E3 ligase and a target protein, leading to ubiquitination and degradation, thereby holding potential for expanding the druggable target space. However, their discovery remains largely serendipitous, hindered by a limited repertoire of E3 ligands (primarily CRBN and DDB1), a lack of predictive models for ternary complex formation, and unclear mechanisms of target selectivity and resistance. To address these bottlenecks, future efforts should focus on establishing AI-assisted screening platforms integrated with high-throughput ubiquitination phenotyping, systematically expanding the E3 ligand toolbox, elucidating ternary complex structures, developing companion diagnostic strategies based on E3 genotypes, and exploring controllable prodrug approaches to enhance the systematic discovery and clinical translation of molecular glues.

Progress in the Development of Hydrophobic Tag-Based Degraders for Various CDK Isoforms

The use of a hydrophobic tag-based degrader (HyT-BD), which consists of a highly hydrophobic group and a small-molecule ligand of the target, is another promising strategy for targeted protein degradation. The hydrophobic tags exposed on the POI surface can be recognized as misfolded or damaged by endogenous chaperones, which results in degradation by the proteasome through protein quality control (PQC).[118] [119] [120] [121] [122] Compared with that of PROTACs and molecular glue degraders, the development of HyT-BD is in an early stage. Even so, some reports still demonstrate the effectiveness of applying hydrophobic tagging technology to induce CDK degradation.

Hydrophobic Tag-Based Degraders of CDK4/6

In 2022, Qiu et al reported the first hydrophobic tag-based degrader of CDK4/6 named LPM3770277 (42, [Fig. 15]), which consisted of abemaciclib and adamantane. Compound 42 induces CDK4/6 degradation via proteasome- and lysosome-promoted autophagy in a concentration- and time-dependent manner. Moreover, 42 showed superior antitumor efficacy and safety compared with those of abemaciclib in a TNBC xenograft model, which demonstrates the viability of using hydrophobic tag-based degraders as a strategy for developing potential treatments.[123]

Fig. 15 Structures of hydrophobic tag-based degraders 42–46 for cyclin-dependent kinases.

Hydrophobic Tag-Based Degraders of CDK8 and CDK9

Wang's group reported the successive application of hydrophobic tag-based degradation strategies for CDK8/Cyclin C and CDK9/Cyclin T1. LL-K8-22 (43, [Fig. 15]) was identified as the first-in-class hydrophobic tag-based dual degrader of CDK8 and Cyclin C based on the structures of BI-1347 and Adamantane. Mechanistic research indicated that 43 could significantly degrade CDK8 and Cyclin C without reducing the levels of CDK19 or other cyclin proteins, which exhibited enhanced antiproliferative activity and more pronounced effects on CDK8–Cyclin C downstream signaling than BI-1347.[124] Furthermore, based on SNS-032, LL-K9-3[125] (44, [Fig. 15]) and LL-CDK9-12[126] (45, [Fig. 15]) were developed for the first application of hydrophobic tagging to induce the degradation of CDK9 and Cyclin T1 using menthol (44) and adamantane (45), respectively. Both degraders showed selective and synchronous degradation of CDK9 (DC₅₀ = 0.662 μmol/L for 44 and DC₅₀ = 0.362 μmol/L for 45) and Cyclin T1 (DC₅₀ = 0.589 μmol/L for 44 and DC₅₀ = 0.683 μmol/L for 45), which exerted stronger antiproliferative and proapoptotic effects than SNS-032 or THAL-SNS-032 (21), as mentioned above. In summary, HyT-BD represents a burgeoning protein degradation area that has the potential to be a new resource for small molecule drugs. However, this topic has not yet been fully explored. Discovering new hydrophobic tags with drug-likeness or auxiliary drug properties and novel applications of hydrophobic tags in CDKs or other cancer-related targets are still worthwhile research directions.

In 2025, our research group reported the first ATG101-recruiting CDK9 degrader, AZ-9 (46, [Fig. 15]), which was developed based on the hydrophobic tag-based Kinesin degradation technology. 46 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1.[127]

Summary of Hydrophobic Tag-Based Degraders

Hydrophobic tag (HyT)-based degraders function by fusing a target protein with a highly hydrophobic moiety, which mimics an unfolded state and leads to recognition by quality control systems (e.g., HSP70/CHIP) and subsequent proteasomal degradation. This approach offers advantages such as low molecular weight, straightforward synthesis, and independence from specific E3 ligases, making it applicable to challenging therapeutic targets. However, its efficacy is constrained by intrinsic protein folding stability and cellular quality control activity, often resulting in suboptimal selectivity, off-target degradation, and cytotoxicity. Additional limitations include rapid in vivo metabolism and a narrow therapeutic window. Current development is hampered by the lack of rational design principles, poor compatibility between the hydrophobic tag and protein binding sites, and insufficient control over in vivo delivery and release. Future efforts should integrate structural biology and computational modeling to optimize tag structure and attachment sites, develop controllable prodrug formats, screen for tissue-specific delivery systems, and establish evaluation standards focused on degradation selectivity to advance the preclinical translation of HyT degraders.

Discussion and Prospects

Since the first report of CDK degraders in 2017, research on CDK-related degradation agents has been ongoing for at least 8 years ([Fig. 16]), which has opened up another popular research field in addition to the development of small molecule inhibitors of CDKs. Numerous experiments have demonstrated the effectiveness of CDK degraders and their potential therapeutic advantages over small molecule inhibitors of CDKs. PROTACs, molecular glues, and hydrophobic tags (HyT) represent three distinct mechanistic paradigms for targeted protein degradation-“bifunctional recruitment,” “interface induction,” and “misfolding mimicry,” respectively. Each class offers unique advantages: the modular architecture of PROTACs enables precise target selectivity and access to “undruggable” proteins; molecular glues, typically under 600 Da, provide favorable oral bioavailability and synthetic tractability; and HyT degraders function independently of specific E3 ligases by co-opting the endogenous PQC machinery. However, their limitations are equally distinct. PROTACs are often hampered by high molecular weight, the hook effect, and a restricted E3 ligase repertoire. Molecular glue discovery remains largely serendipitous due to the absence of reliable predictive models for ternary complex formation. HyT degraders commonly suffer from poor selectivity, considerable cytotoxicity, and rapid in vivo clearance. The clinical translation of these technologies hinges on overcoming key bottlenecks: miniaturizing PROTACs and expanding the toolbox of tissue-specific E3 ligases; establishing AI- and structure-guided rational discovery platforms for molecular glues; and optimizing tag geometry and developing controlled delivery strategies for HyT degraders. Against this backdrop, the development of CDK degraders currently appears particularly promising. Their potential is such that they could, to a significant extent, surpass and eventually replace conventional small molecule CDK inhibitors.

Fig. 16 The development of CDKs-related targeting protein degraders. CDKs, cyclin-dependent kinases.

Presently, from theory to practice, there are still some questions that need to be answered regarding CDK degraders as potential drugs for cancer treatment, which might be research directions worth considering in the future. The first noteworthy issue is the choice of CDK-binding ligands, which should possess high affinity and selectivity for related CDK isoforms. The selective development of small-molecule ligands or degradation agents for specific CDK isoforms is challenging due to the high homology of the CDK family. Targeting the inhibition or degradation of several different CDK isoforms, which might have synergistic effects and reverse the compensatory drug resistance caused by the influence of a single CDK subtype or produce unexpected side effects or toxicity, simultaneously has advantages and disadvantages for the treatment of cancer. Furthermore, selective effects on tumor tissue and normal tissue should be considered in the application of CDK degradation agents. The expression and function of related CDKs are different in normal and tumor tissues, even in different types of tumor tissues. Presently, the in vivo behavior of CDK degradation agents, including the pharmacokinetic properties of absorption, distribution, metabolism, and excretion, which may be affected by factors such as CDK ligand type, form of degradation agent, and linker, has not been fully elucidated. In recent years, the concept of a “Pro-degrader,” which can utilize the differential characteristics between normal and tumor tissues, such as different microenvironments or specific expressed proteins, for controlled drug release, has been proposed for precision medicine.[128] [129] [130] [131] [132] [133] This strategy could also be used in CDK degradation agents for enhanced selectivity.

The development of synthetic processes is another issue that needs to be considered for large-scale use of CDK degradation agents. Compared with those required by small molecule inhibitors, CDK degradation agents require more complex preparation processes due to their more complex molecular structures. However, there are few reports on the synthesis processes of degradation agents, and examples of the optimization of process parameters, traceability of related impurities, and establishment of analysis methods are still lacking.

CDK degraders have been validated to overcome the limitations of traditional inhibitors, including those related to catalytic site dependence and drug resistance, offering a novel therapeutic strategy for tumors driven by aberrant cell cycle progression or transcriptional addiction. We believe that the relevant technologies will continue to be optimized as research progresses, which could make CDK-related degradation agents effective weapons for cancer therapy instead of tools for chemical biology research.

Conflict of Interest

None declared.

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Publikationsverlauf

Eingereicht: 14. April 2025

Angenommen: 10. November 2025

Artikel online veröffentlicht:
11. Dezember 2025