Protacs in oncology: Emerging frontiers in targeted protein degradation

Introduction

Cancer remains one of the leading causes of morbidity and mortality worldwide. Although mortality rates from cardiovascular diseases have declined substantially, cancer-related deaths continue to rise, with nearly 10 million deaths reported annually (Ma and Yu, 2006). According to GLOBOCAN, global cancer incidence increased from 18.1 million new cases and 9.6 million deaths in 2018 to 19.3 million new cases and over 10 million deaths in 2020 (Sung et al., 2021). This escalating burden is attributed to population growth, aging, changing lifestyle and environmental risk factors, and inadequate cancer screening, particularly in low-and middle-income countries (Mathew et al., 2019). India contributes significantly to the global cancer burden, accounting for over 10% of cases worldwide (Chalkidou et al., 2014). Rapid urbanization and lifestyle changes, including increased tobacco and alcohol use, unhealthy dietary habits, and reduced physical activity, have accelerated the incidence of cancer and other non-communicable diseases (Dandona et al., 2017). The World Health Organization reported that one in ten Indians is likely to develop cancer during their lifetime, while one in fifteen may die from the disease. Cancer incidence in India increased from approximately 1.16 million cases in 2018 to 1.39 million in 2020, with further increases projected in the coming years (Mathur et al., 2020). At the molecular level, cancer is driven by mutations that activate oncogenes such as RAS and MYC or inactivate tumor suppressor genes such as p53, leading to uncontrolled proliferation, resistance to apoptosis, metastasis, and metabolic reprogramming (Mallath et International Journal of Advanced Biochemistry Research 2026; SP-10(8): 399-408 al., 2014). Despite advances in treatment, major challenges persist, including drug resistance, tumor heterogeneity, low biomarker specificity, therapeutic toxicity, and the presence of "undruggable" targets. Cancer management encompasses conventional approaches, including surgery, chemotherapy, and radiotherapy, as well as advanced modalities such as immunotherapy, CAR T-cell therapy, precision medicine, ablation therapy, stem cell transplantation, and minimally invasive robotic procedures. Among emerging therapeutic strategies, Proteolysis-Targeting Chimeras (PROTACs) have gained considerable attention. First introduced in 2001, PROTACs represent a transformative approach to targeted protein degradation by harnessing the ubiquitin-proteasome system (UPS) to eliminate disease-associated proteins (Bekes et al., 2022).

Their ability to target proteins previously considered undruggable has positioned them as one of the most promising platforms in modern drug discovery. A PROTAC is a heterobifunctional molecule composed of three essential components: a ligand for the target protein, a chemical linker, and a ligand that recruits an E3 ubiquitin ligase (Wang et al., 2024). By inducing selective ubiquitination and subsequent proteasomal degradation of target proteins, PROTACs offer enhanced specificity, catalytic activity, and the potential to overcome limitations associated with conventional inhibitors, making them highly attractive candidates for next-generation cancer therapeutics. This version is concise, coherent, and suitable as an introduction section for a review article, thesis, or research manuscript on PROTACs in cancer therapy. (Sakamoto et al., 2001). This molecule contained three linked components: a phosphorylated IκBα peptide that recruits the SCF E3 ligase, the MetAP-2 inhibitor ovalicin and a connecting linker. This work established the foundational concept of PROTACsusing the ubiquitin-proteasome system to selectively eliminate target proteins in living cells. Building on this strategy, researchers later developed several peptide-based PROTACs capable of degrading diseaseassociated proteins such as the androgen receptor (AR), estrogen receptor (ER), FKBP12 and AHR (Rodriguez-Gonzalez et al., 2008). These advances demonstrated the potential of peptide PROTACs as highly selective and potent tools for removing overexpressed or pathogenic proteins, opening new avenues for innovative therapeutic development.

Second generation-small-molecule-based PROTACS 3.2.1 PROTACS recruiting different e3 ligases

Recognizing the favorable properties of small molecules, the Crews group developed the first small-molecule PROTAC in 2008, aimed at degrading the androgen receptor (AR) in cancer cells. This design used nutlin-3a, an MDM2-p53 PPI inhibitor to recruit the E3 ligase, while a flutamide-derived selective androgen receptor modulator (SARM) served as the AR-binding ligand. A PEG linker connected the two components. Together, this structure enabled precise recruitment of the ubiquitin ligase complex and promoted efficient AR ubiquitination and degradation (Schneekloth et al., 2008). Fine-tuning the structures and linkers of small-molecule components, researchers can create PROTACs with exceptional selectivity and strong degradation efficiency, enabling precise control over specific target proteins. This progress opens new avenues for innovative drug development and holds great promise for achieving major advancements in treating diseases, including cancer (Buckley et al., 2012).

Third generation -novel PROTACS 3.3.1 Photochemical targeting chimeras

Systemic PROTAC use can unintentionally affect normal cells, causing off-target toxicity. To improve precision, researchers developed Photochemical Targeting Chimeras (PHOTACs), which contain light-removable groups such as nitrobenzyl or azobenzene. Molecules stay inactive in the dark but become active upon UVA or visible light exposure, triggering targeted protein degradation (Reynders et al., 2020). PHOTACs offer superior spatial and temporal control compared to traditional PROTACs and have been shown to degrade proteins like BRD4, FKBP12, IKZF1/3, ALK and BTK. Although promising, challenges such as limited tissue penetration and potential DNA damage from UVA have shifted research toward using safer more suitable light sources for improved PHOTAC design (Wang et al., 2020).

Semiconductor polymer nanoparticle (SPNPRO)

The KanyiPu group introduced SPNpro, a strategy aimed at reducing the off-target toxicity of PROTACs. SPNpro consists of a semiconductor polymer core, cleavable peptide substrates that act as cancer biomarkers, and traditional PROTAC molecules. Under near-infrared light, SPNpro produces reactive oxygen species and initiates anticancer immune responses while its peptide components are cleaved by tumor-associated enzymes such as cathepsin B, releasing active PROTACs to degrade target proteins (Zhang et al., 2021). This system provides strong tumor selectivity and reduced off-target effects, combining photodynamic therapy with targeted protein degradation. Although its large molecular size prevents oral delivery, SPN offers valuable direction for designing integrated cancer therapies.

Novel targeting chimeras

To further enhance PROTAC specificity, several new targeting chimera platforms have been developed. These include folate-linked PROTACs (float-PROTACs) for folate-receptor-positive cancers, antibody-based PROTACs (AbTACs), ribonuclease-targeting chimeras (RIBOTACs), and transcription factor-directed PROTACs (TF-PROTACs) (Liu et al., 2021). Each uses a different targeting mechanism folate receptor binding, antibody selectivity, RNA recognition, or transcription factor interaction to guide degradation toward disease related proteins while reducing effects on healthy cells. Although promising, these systems require extensive experimental and clinical validation to confirm their safety and efficacy (Kargbo, 2021).

Nanocarrier-delivered protacs (NANOPDS)

Nanoparticle-mediated protein degraders (NanoPDs) are emerging as a solution to the limitations of conventional PROTACs. These systems use nanoparticles functionalized with ligands, peptides, or antibodies to direct degradation through either lysosomal pathways or the ubiquitinproteasome system (UPS). Early NanoPDs relied primarily on lysosomal uptake, where nanoparticles bound to membrane proteins are internalized and degraded in endolysosomal compartments (Baker et al., 2025). More advanced designs immobilize ligands for both the protein of interest and an E3 ligase on the nanoparticle surface, enabling proteasomal degradation similar to PROTACs but with enhanced multivalency and local concentration effects. Only VHL and CRBN E3 ligases have been applied in UPS-based NanoPDs. These platforms highlight the potential of nanotechnology to improve targeting precision and degradation efficiency in future therapeutics (Liu et al., 2023).

Mechanism of PROTACs (Proteolysis-Targeting Chimera)

A Protacs (Proteolysis-Targeting Chimera) molecule consists of three essential parts: a ligand that binds the target protein (usually a small-molecule inhibitor), a chemical linker and a ligand that recruits an E3 ubiquitin ligase. These units are joined covalently, commonly through linkers containing approximately 5-15 carbon atoms or other structural elements.

Clinical applications of PROTACS

As of now, there are approximately over ten PROTACs globally in clinical development and there are around 180 preclinical projects (Table 1). The following will provide an introduction with examples focusing on clinical Phase II drugs ARV-110, ARV-471 and Phase I drugs NX-2172, KT-474.

Phase i clinical drug

KT-474

KT-474 is a first-in-class oral PROTAC developed by Kymera Th through TLR or IL-1 receptors, IRAK4 degradation blocks multiple inflammatory pathways at once. Additionally, by removing IRAK4 entirely-not just inhibiting its kinase activity-KT-474 can disrupt both catalytic and scaffolding functions offering broader therapeutic benefit.

Phase ii clinical drug 5.2.1 ARV-110

ARV-110 is an orally active experimental PROTAC designed to selectively degrade the androgen receptor (AR). The AR normally binds testosterone and dihydrotestosterone and after activation, it dissociates from heat shock proteins, dimerizes enters the nucleus, and binds to androgen response elements (AREs) to stimulate gene transcription such as PSA promoting prostate tumor growth. ARV-110 uses PROTAC technology to target and degrade the AR protein, thereby blocking this signaling pathway. It has progressed into clinical development as a promising therapeutic option for metastatic castration-resistant prostate cancer (mCRPC). This drug highlights the potential of PROTACs in advancing prostate cancer treatment. (National Library of Medicine US).

Phase iii clinical drug 5.3.1 ARV-766

Structurally optimized to improve drug properties and tolerability, resulting in overall better performance than ARV-110. Its key enhancements include:

• Linker optimization: replacing the hexagonal ring with a quaternary ring to strengthen binding to mutant AR. • AR ligand modification: substituting chlorine with methoxy groups to improve exposure and tissue penetration.

• CRBN ligand upgrade: switching thalidomide to benzamide to avoid off-target protein degradation (IKZF1/3, GSPT1) and reduce blood toxicity, while increasing plasma stability.

Clinically, ARV-766 shows superior safety, with a low rate (4%) of treatment-related adverse event discontinuation.

ARV-110 confirmed the potential of PROTACs in prostate cancer, its inability to degrade the critical L702H resistance mutation limits its use. ARV-766 overcomes this by degrading a broader range of AR mutations, offering better safety and wider patient applicability. Its development reflects the iterative improvement in PROTAC design and the importance of biomarker-driven precision therapy in advanced cancers (Liu et al., 2022).

ARV-

PROTACS in targeted cancer therapy

Cancer development is driven by a series of interconnected biological processes, including persistent proliferative signaling, evasion of growth-inhibitory pathways, resistance to cell death, stimulation of angiogenesis and the activation of invasion and metastasis (Hanahan and Weinberg, 2011).

Extensive research has shown that many proteins that are overexpressed or abnormally activated play key roles in these processes and therefore represent promising therapeutic targets. PROTAC technology offers a powerful strategy to eliminate such disease-driving proteins. One major application of PROTACs in oncology is targeting aberrant cancer cell proliferation (Samatar and Poulikakos, 2014). Hyperactivation of pathways such as the RAS-RAF-MEK-ERK signaling cascade commonly accelerates cellcycle progression, resulting in uncontrolled tumor growth.

PROTACs have been developed to degrade overexpressed, mutated or hyperactive proteins that regulate the cell cycle, providing a targeted approach for suppressing tumor proliferation.

BRD4

BRD4 is a BET family protein that activates growthpromoting genes like c-myc. Although BRD4 inhibitors (JQ1, OTX015) reduce c-myc, they need high doses and show limited efficacy. PROTACs overcome this by degrading BRD4 instead of just inhibiting it. Early

AURORA-a

Aurora kinase A regulates centrosome separation and the G2-M transition and is overexpressed in several cancers. Nigg (2001) established its oncogenic significance. To overcome limitations of kinase inhibition, Adhikari et al. (2020) developed JB170, an alisertib-VHL PROTAC that induced rapid and selective degradation of AURORA-A in leukemia and neuroblastoma cells. JB170 uniquely caused S-phase arrest, revealing critical non-catalytic roles of AURORA-A in DNA replication. PROTACs are expected to play an increasingly important role as both therapeutic agents and research tools, opening new avenues for targeted protein degradation across multiple diseases.

Conclusion

Since the introduction of the PROTAC concept in 2001, substantial progress has been made to enhance its effectiveness, broaden its target range, and address its limitations. As a result, PROTAC technology has emerged as a promising strategy for cancer treatment. Numerous PROTACs have been developed and have shown clinical potential in controlling tumor progression. Nevertheless, continued efforts are needed to accelerate their advancement. Expanding the spectrum of protein targets remains a major priority in cancer therapy. While inhibitors for certain protein classes, such as kinases, have been successfully developed, many oncogenic proteinsparticularly RNA binding proteins (RBPs) and DNA-binding proteins (DBPs) remain inaccessible to traditional small molecules. Collectively, PROTACs and these emerging degradation technologies represent powerful tools for the selective removal of oncogenic proteins and RNA molecules, and they hold significant promise for future clinical applications in cancer therapy.

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