Chemistry-Driven Integrated Innovation: Unleashing the Potential of PROTAC Technology

Abstract

Proteolysis-targeting chimeras (PROTACs) are driving medicinal chemistry progress, yet efficient synthesis and rational linker design remain two critical bottlenecks for their clinical translation. Those core challenges directly limit the advancement of PROTACs from preclinical research to practical application. This review focuses on state-of-the-art enabling chemical strategies to address these key bottlenecks, ensuring tight relevance to PROTACs development needs. The modular assembly can be streamlined by click chemistry, multicomponent, and late-stage C–H functionalizations, whereas microscale and solid-phase platforms can be used to deliver thousands of analogues in days without purification. In this work, we emphasize covalent sulfonyl fluoride warheads and photocaged or photoswitchable scaffolds that provide spatiotemporal control of degradation. The employment of dynamic combinatorial chemistry, DNA-encoded libraries, and intracellular self-assembly further expands chemical space and accelerates hit triage. At last, we outline how artificial intelligence-driven modeling integrates these data to predict linker length, exit vector geometry, and ADME profiles, shortening iterative design cycles. Collectively, these chemistry-centric innovations are turning PROTACs from a conceptual breakthrough into a practical drug-discovery engine by directly addressing the synthesis, optimization, and functional control challenges that have impeded their clinical advancement.

Keywords

PROTACs - targeted protein degradation - chemistry-driven - integrated innovations

Introduction

Since its inception in the early 2000s, proteolysis-targeting chimera (PROTAC) technology has revolutionized therapeutic strategies by introducing a novel event-driven mechanism. Unlike conventional small molecule therapeutics that rely on high-affinity binding through an occupancy-driven mechanism, PROTACs catalyze the degradation of target proteins via the ubiquitin-proteasome system. This allows for potent biological activity even at sub-stoichiometric concentrations of the targeting ligand.[1] [2] [3] [4] Compared with traditional inhibitors, PROTACs can eliminate proteins that lack deep, well-defined ligandable pockets, such as transcription factors (TFs, e.g., MYC, E2F1), scaffolding proteins, and mutant or overexpressed oncoproteins that have evolved resistance to orthosteric blockade.[5] [6] [7] [8]

Despite their therapeutic potential, PROTACs face substantial challenges in their development. It is well known that the optimization process is demanding and often benefits from high-throughput chemical synthesis coupled to systematic cellular degradation, selectivity, and ADME/Tox assays, although such workflows are not strictly indispensable.[9] [10] A PROTAC is a heterobifunctional molecule composed of three main components: a ligand that binds to the target protein, a linker, and a recruitment ligand that binds to an E3 ubiquitin ligase. The molecular architecture of PROTACs is a critical aspect of their design. Specifically, the optimization of linker length, flexibility, and chemical composition is essential for achieving optimal ternary complex formation. The ternary complex refers to the complex formed between the target protein, the PROTAC, and the E3 ubiquitin ligase. This complex is necessary for efficient ubiquitination and subsequent degradation of the target protein by the proteasome.[11] Moreover, the substantial molecular weight characteristic of PROTACs presents significant pharmacological challenges, particularly in terms of cellular membrane permeability, aqueous solubility, and overall drug-likeness. These physicochemical limitations impose additional constraints on the development of effective degraders, necessitating innovative strategies to optimize their pharmacokinetic profiles while maintaining degradation efficacy.[12]

To address these challenges, a multidisciplinary innovation strategy is essential. Critical to this endeavor is the development of advanced synthetic methodologies capable of efficiently constructing these complex heterobifunctional molecules. The rapid assembly of diverse PROTAC libraries can be achieved by implementing modular synthetic approaches, coupled with combinatorial chemistry strategies. This may involve the establishment of novel synthetic routes or strategic adaptation of existing organic transformations to enhance synthetic efficiency, scalability, and structural diversity.[13] [14] [15]

On the other hand, high-throughput screening methods have been developed to accelerate the evaluation of the biological activity of newly synthesized PROTACs.[16] The design of PROTACs needs to be refined to improve their drug-like properties, ensuring optimal molecular weight for cellular permeability and solubility.[17] And identifying suitable ligands for undruggable targets is another critical area of interest, requiring a deep understanding of protein–ligand interactions to minimize any potential toxic effects.[18] Computational modeling can be utilized to forecast the impact of structures on activities, thereby reducing reliance on empirical methods and saving substantial time and resources.[19]

This perspective does not intend to provide a comprehensive overview of PROTAC applications in therapeutic interventions, as this aspect has been extensively reviewed in the literature.[4] [7] Rather, it focuses on elucidating the pivotal role of innovative chemical strategies in advancing PROTAC technology, with particular emphasis on the integration of cutting-edge synthetic methodologies and rational molecular design principles to overcome existing limitations in the field ([Fig. 1]).

Fig. 1 Illustration of chemical technologies and proteolysis-targeting chimera strategy.

Modular Reactions-Enabled PROTACs

Click Chemistry

The construction of a PROTAC molecule must incorporate two indispensable binding moieties, one that binds to the E3 ubiquitin ligase and the other that binds to the protein of interest (POI). Unlike many designs that rely on preidentified ligands, the design of PROTAC molecules is largely dependent on the linkers, specifically the linkage site, length, flexibility, and chemical composition of the linker.[17] Consequently, linker optimization constitutes a critical step in the chemical synthesis of PROTACs. However, due to the structural heterogeneity and diverse binding topologies exhibited by potential target proteins, linker design presents significant challenges. This necessitates not only extensive synthetic efforts in conventional laboratory settings but also exploration through in situ approaches, thereby underscoring the critical need to establish robust and versatile linking strategies. In this context, “click chemistry” has emerged as a particularly effective platform for the parallel synthesis of diverse PROTAC libraries ([Fig. 2]).[20] [21] For example, the formation of a new triazole ring through the coupling of azides and alkynes through the copper-catalyzed Huisgen 1,3-dipolar cycloaddition reaction. It proved to be ideal due to its biological orthogonality and rapid reaction characteristics.

Fig. 2 General strategy using “click chemistry” for the parallel synthesis of proteolysis-targeting chimeras.

In 2018, Wurz et al proposed a “click chemistry” methodology to assemble PROTACs.[22] As shown in [Fig. 3], this technique can be applied to synthesize bromodomain and extra-terminal domain-4 (BRD4) degraders, utilizing the ligand JQ-1 (1), along with binders for the ligases Von Hippel-Lindau (VHL) and Cereblon (CRBN). In this process, an AlphaScreen proximity assay was employed to assess the formation of the required ternary complex consisting of ligase, PROTAC, and target protein. Additionally, a Meso Scale Discovery platform and a commercially produced detection antibody were implemented to quantify the level of target protein degradation mediated by the PROTACs in cells.

Fig. 3 The employment of “Click Reaction” for the synthesis of PROTACs degrading the BET bromodomain BRD4 protein. BRD4, member of the BET bromodomain family; PROTACs, proteolysis-targeting chimeras.

In 2022, Cross et al utilized “click chemistry” to develop a series of PROTACs based on entinostat, a class I histone deacetylase (HDAC) inhibitor under clinical investigation for solid tumors and hematological malignancies ([Fig. 4]).[23] Among them, a novel compound, JMC-137 (2) demonstrated effective degradation activity against HDAC1/2 and HDAC3 in HCT116 cells. However, comparative analysis revealed its degradation efficacy to be substantially lower than that of previously reported class I HDAC-targeting PROTACs. This finding highlights the critical importance of three key design parameters: optimal selection of HDAC-targeting warheads, strategic positioning of linker attachment points, and precise spatial orientation in the ternary complex architecture, collectively underscoring the intricate nature of PROTAC optimization. Notably, the application of click chemistry has recently been extended to the development of degraders targeting oncologically relevant proteins, including glutathione peroxidase 4 (GPX4) and peptidyl-prolyl cis–trans isomerase NIMA-interacting 1 (PIN1), demonstrating its versatility in PROTAC discovery (3 and 4, [Fig. 4]).[24] [25]

Fig. 4 The employment of “Click Reaction” for the synthesis of representative proteolysis-targeting chimeras.

Each triazole formed by CuAAC constitutes a geometrically defined and metabolically stable linker whose length and flexibility were systematically varied in the reported libraries. The degradation structure–activity relationship (SAR) across these series directly demonstrates that incremental one-carbon or polyethylene glycol extensions, and the rigidity imparted by the triazole itself, can modulate the stability and cellular potency of the ternary complex, thereby illustrating how click chemistry rapidly probes and optimizes linker parameters without resynthesizing entire molecules.

Multicomponent Reactions

“Click chemistry” allows for the efficient production of VHL- and CRBN-based degraders. However, the incorporation of the triazole ring may yield poorly soluble products and posing challenges in the scaling-up process.[26] The synthetic assembly of PROTACs requires precise asymmetric functionalization of linker architectures and their regioselective conjugation with protein-binding motifs, presenting a significant chemical challenge. This synthetic complexity typically mandates the employment of orthogonal chemical strategies or multistep protection/deprotection protocols to ensure controlled molecular assembly and structural integrity.

In 2022, Bhela et al reported an innovative multicomponent reaction-based platform, based on the modular characteristics of multicomponent reaction systems coupled with targeted protein degraders to facilitate the synthesis of structurally elaborated PROTACs.[27] Aldehyde, isocyanide, and carboxylic acid building blocks are combined using a one-pot Passerini three-component reaction to form the entire linker–warhead segment, generating BRD4-degrading PROTAC (9) and congeners in a single operation. As a proof of concept, the platform has been utilized for the synthesis of PROTAC-based BRD4 degraders, leading to the identification of a series of degraders exhibiting remarkable degradation efficiency ([Fig. 5]).

Fig. 5 The versatile and sustainable multicomponent platform for the synthesis of protein degraders.

In 2023, Zhu et al developed a novel activity-based PROTAC probe PD-Q2 via the Ugi reaction, assembling the GPX4 inhibitor ML-162 with features of the cereblon ligand pomalidomide.[28] As illustrated in [Fig. 6], the desired compound was synthesized as a racemic mixture through a four-component Ugi reaction. Validation studies confirmed the covalent engagement of GPX4 by PD-Q2, while revealing limitations in degradation efficiency that prompted further optimization. Mechanistically, these compounds induced a significant accumulation of lipid reactive oxygen species (ROS), resulting in profound suppression of clonogenic potential and proliferation kinetics in cancer cells.

Fig. 6 The design of PROTAC-like active probes using a Ugi reaction. PROTAC, proteolysis-targeting chimera.

In addition to the aforementioned one-pot synthesis method, Arndt et al reported a one-pot, visible-light-driven decarboxylative C(sp² )–C(sp³ ) coupling that directly joins a brominated CRBN ligand to a JQ-1-derived carboxylic acid, furnishing a single PROTAC in 55% yield.[29] As shown in [Fig. 7], this consolidated methodology enables streamlined generation of PROTAC libraries in one pot by covalently linking a CRBN E3 ubiquitin ligase recruiter to JQ-1 (serving as the target protein binder) through various linker types-flexible aliphatic chains, aromatic systems, and rigidified bridging units. Notably, this streamlined protocol significantly accelerates the construction of targeted protein degradation tools.

Fig. 7 One-pot synthesis of PROTAC from three components via photoinduced C(sp2)-C(sp3) coupling and amidation. PROTACs, proteolysis-targeting chimeras.

Late-Stage Functionalization

In the last several years, late-stage functionalization has made significant progress and emerged as a powerful approach for the diversification and assembly of increasingly complex molecules.[30] Recent progress in transition metal-catalyzed C–H functionalization has unlocked novel bond-forming strategies with enhanced atom- and step-efficiency, significantly broadening medicinal chemistry's synthetic repertoire. Antermite et al presented a robust ruthenium-catalyzed late-stage C–H amidation strategy that allows for the synthesis of fully elaborated heterobifunctional compounds ([Fig. 8]).[31] The strategic utilization of commercially accessible dioxazolone reagents enables site-selective C–H amidation on structurally complex bioactive molecules, guided by inherent directing groups. This transformation exhibits remarkable functional group compatibility and regioselectivity, facilitating the late-stage incorporation of linker moieties equipped with orthogonal reactive handles for downstream derivatization. Notably, the authors successfully demonstrated the versatility of this approach through the efficient one-pot synthesis of both CRBN-recruiting and biotinylated conjugates, underscoring the methodology's potential for streamlined production of sophisticated therapeutic agents and chemical probes.

Fig. 8 Synthesis of PROTAC-like compounds via late-stage C–H amidation. PROTAC, proteolysis-targeting chimera.

Microscale Synthesis-Enabled PROTACs

The bottleneck in developing PROTAC workflows lies not only in efficient synthesis but also in the subsequent purification steps, which are often time-consuming and resource-intensive while simultaneously limiting the speed of iterative optimization. To address this challenge, Stevens et al developed an ultra-high-throughput experimentaion (ultraHTE) system. This represents a core innovation of microscale synthesis for PROTACs, integrating two critical functions: facilitating rapid PROTAC synthesis and enabling immediate biological evaluation of unpurified reaction products in cellular degradation assays ([Fig. 9]).[32] This innovative “direct-to-biology” (D2B) strategy was successfully validated through a medicinal chemistry initiative focused on discovering new BRD4-targeting PROTACs. Via the strategy, researchers synthesized 650 PROTACs in a 1,536-well plate and performed biological evaluations within less than 1 month. The process involved dosing stock solutions onto a 384-well plate, followed by robotic dispensing into the 1,536-well reaction plate; aliquots were analyzed by liquid chromatography–mass spectrometry using PyParse, and successful reactions were directly advanced to cellular assays without additional purification steps. Compounds of interest were resynthesized for further profiling, with SAR guiding the next iteration of the compound design. Given its remarkable capability to significantly expedite new degrader optimization processes, it is anticipated that this platform will revolutionize both synthesis and testing aspects associated with PROTAC development.

Fig. 9 A fully automated discovery platform of PROTACs from crude reaction mixtures. PROTACs, proteolysis-targeting chimeras. Reproduced with permission from Stevens et al.[32]

The precise determination of length, shape, and linker attachment points is crucial for designing effective PROTACs. To expedite the identification of potential hits, Plesniak et al exploited a library of established E3–ligand–linker intermediates, introducing a parallel synthesis and purification procedure for PROTAC screening ([Fig. 10]).[33] A high-throughput nanomole-scale synthesis platform has been developed utilizing amide coupling chemistry enabled by a low-loading palladium catalyst and green solvent system that suppresses side reactions and boosts conversion efficiency. This platform enables direct biological evaluation of crude reaction mixtures and simultaneous determination of critical physicochemical parameters, including lipophilicity (logD) and exposed polar surface area (PSA). This innovative approach dramatically accelerated PROTAC SAR exploration, reducing the optimization cycle from several weeks to merely 5 days while eliminating the need for extensive purification procedures. Relying on the above amide coupling innovations, the implementation of this cost-effective and sustainable nanoscale synthesis paradigm has significantly expedited the discovery of PROTAC leads, as the platform's efficiency stems from the coupling system's selectivity, exemplifying how such synthetic chemistry advancements facilitate the realization of PROTAC technology's therapeutic potential.

Fig. 10 Rapid PROTACs discovery platform based on the nanomole-scale array synthesis and direct screening of reaction mixtures. PROTACs, proteolysis-targeting chimeras.

In 2024, Tian et al introduced a miniaturized, high-throughput platform integrating solid-phase synthesis and biological screening for PROTACs.[34] The developed on-chip methodology uses ultraviolet (UV)-induced release in direct experimental procedures and has facilitated the successful synthesis and characterization of 132 novel PROTAC-like molecules with minimal consumption of reagents. In addition, it is compatible with cancer cell cultivation and mitogen-activated protein kinase kinase inhibition determinations, and therefore, provides an efficient approach to accelerate PROTAC optimization and drug development.

Guo et al described a novel Rapid-TAC platform that streamlines PROTAC synthesis through direct coupling between the O-dibenzaldehyde group on a protein ligand and amine groups in a commercial PROTAC library.[35] This approach enables quick assembly of functional PROTACs for immediate screening, with lead degraders (e.g., AR-RapidTAC-1, BRD4-RapidTAC-2) featuring diimine linkers that support ternary complex formation. The platform's efficacy was demonstrated through the rapid identification of potent androgen receptor (AR) and BRD4 degraders. The inherent versatility of the Rapid-TAC platform holds promise for significantly expanding its utility in drug discovery paradigms, streamlining PROTAC accessibility, and optimizing SAR investigations. This technological advancement exemplifies how innovative chemical methodologies can enhance the therapeutic landscape of targeted protein degradation, potentially accelerating the translation of PROTAC-based therapeutics from bench to bedside.

Yan et al proposed a direct-to-biology platform for the efficient synthesis of plate-based PROTAC libraries. This platform eliminates post-synthesis purification by ensuring reaction mixtures have low toxic byproducts and good biocompatibility, thereby enabling direct application in cell-based assays.[36] Specifically, it integrates amide coupling (to link ligand fragments with a molecular linker) and light-induced primary amines and o-nitrobenzyl alcohols cyclization photoclick chemistry, forming a modular PROTAC assembly workflow. This workflow facilitated the rapid identification of potent PROTACs that selectively degrade the kinase CDK9 and suppress triple-negative breast cancer cell growth. By streamlining the process, the approach enhances chemical space exploration, accelerates novel PROTAC discovery, and thus improves drug development efficiency.

Dynamic Combinatorial Chemistry-Enabled PROTACs

The dynamic combinatorial chemistry (DCC) platform enables efficient generation of molecular libraries with sophisticated architectures, demonstrating broad applicability in both medicinal chemistry and supramolecular science.[37] [38] DCC builds reversible libraries ([Fig. 11]) from interchangeable building blocks under thermodynamic control. The introduction of a target macromolecule as a template shifts the equilibrium, selectively amplifying the strongest binders. Enrichment factors that quantitatively rank affinity and selectivity can be obtained by comparing templated and nontemplated mixtures, allowing rapid identification of PROTACs or other ligands for enzymes, membrane receptors, transmembrane proteins, and nucleic acids alike.

Fig. 11 The schematic representation of the DCC concept for PROTAC screening. DCC, dynamic combinatorial chemistry; PROTAC, proteolysis-targeting chimera.

In recent years, the DCC platform has been progressively adapted for PROTAC discovery, utilizing its capacity to selectively stabilize the most effective ternary complexes from dynamic libraries. Diehl et al created a novel DCC strategy for PROTAC selection, utilizing thermodynamic stabilization of the target–E3 ligase–PROTAC ternary assembly as the key criterion.[39] Their focus lies in utilizing VHL-targeting Homo-PROTACs as a model system. They demonstrated that the reversible assembly of a VHL Homo-PROTAC ternary complex through thiol-disulfide exchange chemistry leads to potent amplification of VHL Homo-PROTACs with degradation activities strongly correlated with their biophysical capacity to dimerize VHL.

Self-Assembly-Enabled PROTACs

The development of intracellular self-assembled PROTACs technology addresses challenges in clinical translation, such as limited penetration, inadequate degradation, and potential DNA damage caused by UV radiation. Lebraud et al proposed the concept of click-formed proteolysis targeting chimeras (CLIPTACs, [Fig. 12]), wherein two small precursor molecules capable of undergoing click reactions within cells exhibit enhanced cellular membrane permeability compared with a single large compound.[40] They created a thalidomide derivative labeled with tetrazine, which quickly reacts with a ligand of the target protein tagged with trans-cyclo-octene within cells to produce a cereblon E3 ligase recruiting a PROTAC molecule. In this work, the developed CLIPTAC precursors exhibit substantially lower molecular weight and reduced PSA relative to literature-reported BRD4-targeting PROTACs, as demonstrated by a comparative analysis. The successful degradation of BRD4 and ERK1/2 in three different cell lines, along with corresponding control experiments, confirms the hypothesis that CLIPTACs can be generated within cells through click reactions involving trans-cyclooctene (TCO)-ligands (17) and Tz-thalidomide (19).

Fig. 12 The scheme explaining the mode of action of click-formed proteolysis-targeting chimeras CLIPTACs.

In 2023, Gui et al addressed PROTAC challenges such as cellular permeability, solubility, and “hook effect” with the aim of optimizing PROTACs' therapeutic properties.[41] Self-assembled PROTACs were designed to efficiently degrade the VHL E3 ubiquitin ligase via a rapid, reversible covalent bonding mechanism between hydroxylamine and aldehyde groups, thus enhancing their in vivo therapeutic potential without the “hook effect.” Recently, Giardina et al modified their Coferon platform to create small molecule degraders called Combinatorial Ubiquitination REal-time PROteolysis (CURE-PROs).[42] These CURE-PROs self-assemble into covalent heterodimers through reversible bio-orthogonal linkers, incorporating phenylboronic acid and diol/catechol moieties into ligands for VHL, CRBN, mouse double minute 2 (MDM2), etc. This approach enabled the degradation of BRD4 both in vitro and in vivo. The combinatorial design facilitated compound synthesis, optimized linker length, and identified suitable E3 ligase partners for each target, making it ideal for screening new targets.

Concerns have arisen regarding the possible adverse effects of compounds generated using this approach due to uncontrolled protein degradation and undesired off-target effects mediated by ligases. The precise manipulation of the PROTAC degradation activity could mitigate their potential toxicity and side effects. Chang et al have developed a bio-orthogonal prodrug strategy called click-release “crPROTACs” that enables targeted activation of PROTAC prodrugs and selective release of PROTACs in cancer cells ([Fig. 13]).[43] Inactive TCO-DT2216 and TCO-ARV-771 PROTAC prodrugs were rationally designed by incorporating a bio-orthogonal TCO group into the VHL E3 ubiquitin ligase ligand. The tetrazine (Tz)-modified RGD peptide, c(RGDyK)-Tz, which targets integrin α_vβ₃ biomarkers in cancer cells, serves as the activating component for click-release of PROTAC prodrugs to achieve targeted degradation of POIs, specifically in cancer cells rather than noncancerous normal cells.

Fig. 13 The bio-orthogonal PROTAC prodrug strategy enabled by on-target activation. PROTAC, proteolysis-targeting chimera.

Epigenetic regulation has been successfully used in therapeutic targeting of BET proteins to correct pathological protein imbalances in cancer treatment. Nevertheless, creating tumor microenvironment-responsive BET degraders that combine precise targeting with optimal drug-like properties remained a significant challenge. In 2022, Do et al reported enzyme-derived clicking PROTACs (ENCTACs), capable of orthogonally cross-linking two distinct small molecule warhead ligands. These specifically recognize BRD4 protein and E3 ligase within tumors only upon hypoxia-induced activation of nitroreductase enzyme ([Fig. 14]).[44] The spatially restricted generation of these bifunctional degraders enables targeted BRD4 suppression, leading to coordinated epigenetic reprogramming and controlled manipulation of hypoxia response pathways across cellular, zebrafish, and murine tumor models.

Fig. 14 Enzyme-derived click formation of heterobifunctional degraders of BRD4. BRD4, a member of the BET bromodomain family.

TFs are proteins that regulate gene expression by binding to specific DNA sequences.[45] TFs dysregulation is associated with cancer, neurodegenerative disorders, cardiovascular diseases, and other human diseases. TFs targeting offer potential therapeutic benefits by modulating gene expression in a disease-specific manner; however, for several decades, despite remarkable progress in understanding their biological functions and even elucidating their crystal structures, targeting the majority of TFs has remained an insurmountable challenge. Liu et al devised a TF-PROTACs platform in which a DNA oligonucleotide is linked to a VHL ligand via a copper-free SPAAC click reaction between an azide-functionalized DNA (N3-ODN) and a DBCO-bearing VHL ligand (VHLL) ([Fig. 15]).[45] The resulting triazole conjugate selectively recruits VHL to the TF recognized by the DNA sequence, triggering degradation. Notably, two series of VHL-based TF-PROTACs named E2F-PROTAC (dE2F) and NF-κB-PROTAC (dNF-κB) were designed. These compounds were effective in degrading endogenous E2F1 and p65 proteins in cellular models, exhibiting remarkable antiproliferative effects. These findings highlight the potential utility of TF-PROTACs as a versatile platform for achieving targeted TF degradation and provide a universal strategy for addressing previously “undruggable” TF targets.

Fig. 15 The schematic diagram of the TF-PROTAC strategy.

DNA-Encoded Library-Enabled PROTAC

The DNA-encoded library (DEL) represents a highly efficient technology for the parallel synthesis and screening of millions or billions of compounds through affinity selection. This efficiency stems from its ability to rapidly identify high-affinity binders from large chemical spaces, making it a powerful tool for drug discovery. The DEL affinity selection process fully meets the requirements for affinity-based PROTAC discovery. Chen et al employed DEL technology to synthesize a broad range of potential PROTAC molecules while presenting a parallel screening approach that employs DNA barcodes as indicators for ternary complex formation and cooperative binding ([Fig. 16]).[46] The process involves synthesizing a diverse library of PROTACs, each tagged with a unique DNA barcode, and then incubating the library with the target protein and E3 ligase complex to form ternary complexes. Through affinity selection and next-generation sequencing of the DNA barcodes, the most effective PROTACs that stabilize the ternary complex are identified, thereby optimizing the design for target protein degradation. Additionally, they employed a designed PROTAC DEL targeting CRBN and BRD4 to demonstrate a dual protein affinity selection method, leading to the direct discovery of novel and potent BRD4 PROTACs. This approach facilitated the simultaneous evaluation of all potential PROTACs while overcoming issues related to solubility and permeability interference.

Fig. 16 The optimization of PROTAC ternary complex using DNA encoded library approach. PROTACs, proteolysis-targeting chimeras. Reproduced with permission from Chen et al.[46]

Therapeutically relevant small molecules that stimulate protein complex formation offer precise means to modulate essential cellular functions. Mason et al have developed a platform for the direct discovery of compounds capable of inducing association between any two preselected proteins, utilizing the E3 ligase VHL and bromodomains as test systems.[47] By harnessing the screening capabilities of DELs, they synthesized approximately one million compounds with a VHL-targeting ligand, various connectors, and a diversity element generated through split-and-pool combinatorial chemistry. Through screening the DEL against bromodomains in the presence and absence of VHL, they successfully identified molecules that bind to VHL while simultaneously bound to bromodomains. The research provided a methodological framework for utilizing DEL screening to discover heterobifunctional small molecules.

Solid-Phase Synthesis-enabled PROTACs

The development of HDAC degraders has attracted significant interest, with a few HDAC degraders being disclosed in recent years. In 2022, Sinatra et al used a combination of solution- and solid-phase parallel synthesis protocols to obtain a series of HDAC6 degraders based on nonselective and HDAC6-selective ligands, which involved preparing key intermediates through solution-phase synthesis, constructing peptide chains and coupling CRBN ligands on resin through solid-phase synthesis, and finally releasing the target PROTAC through cleavage reaction. The most potent compounds were efficiently screened ([Fig. 17]), combined with the parallel synthesis strategy.[48] According to the previously published approach, PROTAC synthesis was accomplished by coupling the E3 ligase component using hydroxamic acids immobilized on resins, followed by cleavage from the resin under gentle conditions that generated hydroxamic acids with excellent crude purities up to 91%. Before biological evaluation, compounds were further purified above 95% purity, using preparative reversed-phase high-performance liquid chromatography, rendering PROTAC derivatives with total yields ranging from 27 to 71%. Overall, this synthetic strategy facilitated the quick and efficient generation of PROTAC libraries.

Fig. 17 Solid-phase synthesis of HDAC6 PROTACs. The hydroxamic acid warhead is first attached to Rink-amide resin via an oxygen linker, followed by Fmoc-based peptide elongation, on-resin CRBN ligand coupling, and TFA cleavage to release the final PROTAC. CRBN, cereblon; HDAC6, histone deacetylase 6; PROTACs, proteolysis-targeting chimeras.

Sulfonyl Fluoride-Based Covalent PROTACs

Covalent ligand-directed PROTACs targeting E3 ubiquitin ligases have emerged as a promising strategy in targeted protein degradation. Structural studies have elucidated that the hydroxyproline moiety in VHL ligands forms a critical hydrogen bonding interaction with the Ser110 residue, which is essential for molecular recognition. To expand the substrate range of covalent E3 ligase PROTACs, Shah et al developed VHL-SF2 (27, [Fig. 18A]), a heterobifunctional degrader that replaces the native hydroxyl with a sulfonyl fluoride warhead, covalently targeting Ser110 of VHL, linked via a flexible alkyl chain to an APT1-directed hydroxamate.[49] This study first demonstrated covalent VHL ligands that can be seamlessly integrated into bifunctional degrader architectures, thereby significantly expanding the targetable proteome for covalent E3 ligase-engaging PROTACs. The development of these novel covalent warheads strategically expands the chemical toolbox for targeted protein degradation, enabling access to previously undruggable protein targets through covalent engagement strategies.

Fig. 18 (A) The structure of covalent targeted-VHL (26) probe VHL-SF2 (27) with a sulfonyl fluoride moiety. (B) General model of sulfonyl fluoride PROTACs. PROTACs, proteolysis-targeting chimeras; VHL, Von Hippel-Lindau.

PRosettaC software has been recently used to optimize the design of a sulfonyl-fluoride-based PROTAC linker targeting acyl protein thioesterase 1 (APT1).[50] The computational approach proposed alkyl linkers for APT1 ([Fig. 18B]), which were experimentally validated for effective APT1 degradation and selectivity among serine hydrolases. The integration of PRosettaC with chemoproteomics provides a strategy for efficient PROTAC candidate prioritization and assessment, enhancing the design process and accelerating targeted protein degrader development.

Photocontrolled PROTACs

PROTAC molecules may exhibit an event-driven behavior at low doses, thereby partially mitigating high-dose-related toxicity. Nevertheless, controlling their activity through dosage remains challenging due to their potent catalytic mechanism. Furthermore, PROTACs retain the risk of off-target effects like small molecule inhibitors. To address this issue, researchers are endeavoring to use photoregulation techniques to precisely regulate protein degradation with high spatiotemporal resolution, thereby minimizing potential systemic side effects.[51]

Li et al synthesized a series of pomalidomide analogs by substituting the photocage group 6-nitroveratryloxycarbonyl with the glutarimide group at the C-terminal of pomalidomide ligand CRBN of E3 ubiquitin ligase and subsequently conjugating them to BET inhibitors through appropriate linkers to obtain a series of PC-PROTACs ([Fig. 19]).[52] The presence of the photocage group hindered protein degradation, but upon irradiation with 365 nm UV light, it could be reactivated and induce degradation again. At a concentration of 1 μmol/L, PC-PROTAC completely degraded BRD3 protein in HEK293FT cells after 15 minutes of UV irradiation, demonstrating superior in vitro antitumor activity compared with the nonirradiated control group.

Fig. 19 Representative photo-controlled proteolysis-targeting chimeras.

Nicotinamide adenine dinucleotide (NAD⁺) is an indispensable coenzyme in DNA synthesis and possesses diverse biological functions. Nicotinamide phosphoribosyltransferase (NAMPT) is the key rate-limiting enzyme involved in NAD⁺ biosynthesis in mammals.[53] Cheng et al developed a pioneering chemical tool for the optical manipulation of NAMPT and NAD⁺ in biological systems using photoswitchable proteolysis-targeting chimeras (PS-PROTACs, [Fig. 19]).[54] By employing an NAMPT activator and a dimethylpyrazolazobenzene photoswitch, highly efficient PS-PROTACs were designed, enabling reversible up- and downregulation of NAMPT and NAD⁺ in a light-dependent manner while mitigating the toxicity associated with inhibitor-based PS-PROTACs. Under irradiation at 620 nm, PS-PROTAC was activated, thereby achieving optical control of antitumor activity, NAMPT, and NAD⁺ through in vivo manipulation.

Jin et al developed azobenzene-proteolysis targeting chimeras (Azo-PROTACs, [Fig. 19]) as a novel small molecule tool to manipulate the protein degradation process using UV light.[55] By employing the lenalidomide-Azo-dasatinib trifunctional system, they demonstrated distinct differences in protein degradation activity between the trans- and cis-isomers of Azo-PROTACs. This system enables precise degradation of ABL and BCR-ABL proteins through configuration changes induced by UV-C light exposure. Azo-PROTACs combine potent protein knockdown capabilities and efficient cell uptake properties with reversible photo-switchability, proposing a promising chemical knockdown strategy based on light-induced reversible on/off modulation.

Naro et al pioneered light-responsive PROTAC systems through targeted modification of VHL- and CRBN-recruiting ligands with photolabile caging groups, enabling optical regulation of protein degradation activity ([Fig. 19]).[56] By installing photolabile caging groups onto the E3 ligase ligands of PROTACs, the activity of protein degradation can be regulated by light. This method employs UV/VIS light of a specific wavelength (365 nm) to remove the caging groups, thereby activating the protein degradation function of PROTACs. This approach provides a powerful tool for studying protein function and developing new therapeutic strategies.

Artificial Intelligence-Driven Innovations in PROTAC Development

PROTACs have revolutionized targeted protein degradation, providing a novel therapeutic strategy for previously “undruggable” proteins; however, their development is hindered by challenges like complex linker design, pharmacokinetic property optimization, and the demand for high-throughput screening. In recent years, artificial intelligence (AI) and machine learning (ML) have emerged as powerful tools to address these issues, accelerating PROTAC discovery and optimization. Specifically, AI-driven approaches optimize PROTAC design by using computational models to predict how structural modifications affect activity-reducing reliance on empirical methods and saving time and resources. For instance, the PROTACable platform integrates three-dimensional structural modeling with advanced ML algorithms for automated PROTAC design, enabling efficient identification of lead compounds with improved ADME characteristics and therapeutic potential.[19] This approach leverages AI to analyze large datasets, yielding insights into linker design, target specificity, and degradation efficiency.

AI-driven predictive modeling has also been applied to enhance the drug-like properties of PROTACs. AI-driven predictive modeling can use the data from techniques like nuclear magnetic resonance spectroscopy, molecular dynamics simulations, and principal component analysis to predict the cell permeability of PROTACs based on their structural properties ([Fig. 20]). These models help in the rational design of PROTACs with improved pharmacokinetic profiles, addressing challenges such as high molecular weight and poor solubility.[12] By integrating AI with chemoproteomics, researchers can further refine PROTAC candidates, ensuring they meet the necessary criteria for clinical translation.

Fig. 20 Artificial intelligence-driven predictive modeling. Reproduced with permission from Poongavanam et al.[12]

Summary

PROTACs represent a transformative therapeutic modality, yet their clinical translation is hindered by challenges in molecular design, synthesis, and biological evaluation. This section focuses on chemistry-driven innovations that address these hurdles, paving the way for next-generation protein degraders.

Click chemistry and multicomponent reactions address critical challenges in linker design, where length, flexibility, and composition determine therapeutic efficacy. Those techniques enable precise modulation of linker properties. Microscale platforms and direct-to-biology approaches streamlined labor-intensive purification in traditional synthesis, accelerating high-throughput production. Selectivity and off-target effects are mitigated via chemistry-based strategies, e.g., DCC, self-assembled PROTACs, and covalent PROTACs. DELs and solid-phase synthesis overcome limitations in cellular permeability and solubility, while photocontrolled PROTACs achieve spatiotemporal degradation control, reducing systemic toxicity.[57]

The integration of chemical-driven innovations with advanced computational and biological tools plays a key role. The application of AI and deep learning in PROTAC design holds the potential to revolutionize the field by enabling the rational design of degraders with optimized pharmacokinetic and pharmacodynamic properties. AI-driven models can predict the impact of structural modifications on PROTAC activity, reducing the reliance on empirical methods and accelerating the discovery process. Moreover, the combination of PROTACs with other drug discovery strategies, such as multivalency,[58] multitargeting,[59] [60] prodrug strategy,[61] aptamer,[62] antibody conjugation,[63] [64] etc., has expanded the scope of protein degradation beyond traditional small molecule inhibitors. The integration of PROTACs with other drug discovery strategies showcases the versatility of this technology in addressing complex biological challenges, thereby presenting a novel paradigm characterized by “integrated medicinal chemistry.” Integrated innovation will be a prominent trend in contemporary drug discovery, where pioneering research findings often arise from the combination of two or more strategies or technologies.[65] This tendency is particularly evident within the field of PROTAC technology.

In summary, chemistry-driven strategies are the cornerstone of PROTAC advancement. To date, innovations in linker chemistry, synthetic methodologies, and controlled degradation have overcome some key barriers, bringing clinical translation closer. Nevertheless, ongoing progress in chemical design remains essential and will be pivotal to addressing remaining obstacles and unlocking PROTACs' full therapeutic potential.

Conflict of interest

None declared.

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Publication History

Received: 24 January 2025

Accepted: 24 October 2025

Article published online:
15 December 2025