Aug 2026· Theoretical and Natural Science· Vol 184, pp. 58-64· 0 citations
TL;DR
Optimized ligand-linker design, tumor-selective E3 ligases, prodrug strategies and biomarker-guided clinical trials are expected to greatly promote the clinical development of PROTAC-based anticancer therapies.
Abstract
Traditional small-molecule anticancer inhibitors primarily block single protein activities and are vulnerable to mutation-mediated drug resistance. Proteolysis-targeting chimera (PROTAC) technology induces the ubiquitin-proteasome-dependent clearance of oncogenic proteins and provides a promising new strategy for precision cancer therapy. This paper summarizes the molecular basis, degradation mechanism, design principles, and translational progress of PROTAC degraders in cancer treatment. PROTACs consist of a target ligand, an E3 ubiquitin ligase ligand and a connecting linker, and they exert unique event-driven antitumor effects by inducing ternary complex formation and target ubiquitination. Representative ER, AR, BTK, BCL-xL, and BRD4 degraders have shown promising preclinical or clinical activity, especially in drug-resistant tumors. Current challenges include poor oral pharmacokinetic properties, incomplete tumor selectivity, uncertain long-term safety, and emerging resistance mechanisms related to ubiquitin signaling. Optimized ligand-linker design, tumor-selective E3 ligases, prodrug strategies and biomarker-guided clinical trials are expected to greatly promote the clinical development of PROTAC-based anticancer therapies.
This thorough analysis investigates the molecular basis of PROTAC technology, tracking its progression from an elegant intellectual notion to a clinically approved treatment platform and provides a detailed survey of the current clinical landscape.
N. Vijaya Lakshmi Reddy, M. Sarika, V. Deepika et al.· International Journal of Adv...· 0 citations
Colorectal cancer (CRC) is among the most common malignancies worldwide, and advanced or metastatic disease remains difficult to treat because of tumor heterogeneity, adaptive resistance, pathway redundancy, drug-related toxicity, and limited predictive biomarkers. Small-molecule kinase inhibitors (SMKIs) provide therapeutic opportunities for selected molecular subgroups by targeting key signaling pathways, but their clinical application is still constrained by complex resistance mechanisms, off-target toxicity, and insufficient biomarker-guided stratification. This narrative review summarizes recent progress in SMKIs for CRC, including molecular targets, clinical evidence, resistance mechanisms, combination strategies, and translational directions. Emerging technologies, including multi-omics profiling, artificial intelligence-assisted drug discovery, patient-derived models, liquid biopsy, molecular imaging, multidrug delivery systems, and adaptive trial designs, can be integrated into a translational “discover–validate–monitor–adapt” workflow and may help address some current limitations in targeted drug development for CRC. Future development of SMKI-based therapy in CRC will require biomarker-guided patient selection, rational combination strategies, dynamic monitoring of resistance, and prospective validation using clinically meaningful endpoints.
Lei Liu, Yingjun Chen, Mingxin Guo et al.· Frontiers in Pharmacology· 0 citations
Selective cyclin-dependent kinase (CDK) 4/6 inhibitors play a leading role in the treatment of breast cancer; however, their efficacy is often limited by acquired resistance. Proteolysis-targeting chimera (PROTAC) technology has recently emerged as a promising therapeutic strategy to overcome drug resistance. In this study, we designed and synthesized a series of novel CDK4/6 PROTACs based on dalpiciclib incorporating rigid linkers. The optimal compound P11 exhibited potent and selective CDK4/6 degradation activity mediated by the ubiquitin-proteasome system. Binding model analysis demonstrated that P11 is capable of forming a stable CDK6-CRBN-P11 ternary complex. P11 significantly inhibited proliferation and colony formation, and induced cell cycle arrest in breast cancer cell lines. Furthermore, P11 effectively suppressed tumor growth in an MCF-7 xenograft model, demonstrating stronger anti-breast cancer activity than dalpiciclib both in vitro and in vivo. Importantly, P11 showed potential to overcome acquired resistance to CDK4/6 inhibitors. Therefore, P11 could be a promising preclinical candidate for further development.
Guoyong Pan, You Li, Jinke Tan et al.· Bioorganic chemistry (Print)· 0 citations
Melanoma remains one of the most aggressive malignancies, with limited response to immune checkpoint inhibitors (ICIs) due to primary or acquired resistance. Proteolysis-targeting chimeras (PROTACs) have emerged as a novel therapeutic modality that induces selective degradation of target proteins via the ubiquitin–proteasome system, offering distinct advantages over conventional inhibitors. This review summarizes the design principles and molecular mechanisms of PROTACs, and highlights their emerging role in sensitizing melanoma to immunotherapy. Specifically, PROTACs can restore tumor antigen presentation, reprogram the immunosuppressive tumor microenvironment by targeting regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, and suppress key oncogenic signaling pathways. We also discuss combination strategies with PD-1/PD-L1 and CTLA-4 blockade, as well as current challenges including poor cell permeability, off-target effects, and acquired resistance. Finally, future perspectives on rational design, tissue-specific delivery systems, and clinical translation are addressed.
Qiujun Zhou, Xiaowei Zhang, Chenlu Zhao et al.· Journal of Experimental &...· 0 citations
Therapy resistance in gastrointestinal tumors remains a critical challenge in clinical oncology, severely compromising therapeutic efficacy and long-term patient survival. E3 ubiquitin ligases, as core enzymes involved in the protein ubiquitination process, have been demonstrated to play indispensable roles in regulating key biological processes in tumor cells, including DNA damage repair, cell cycle progression, apoptosis, cancer stem cell maintenance, and immune evasion. Additionally, E3 ligases are key regulators of resistance to multiple anticancer strategies, such as chemotherapy, radiotherapy, targeted therapy, and immunotherapy. This review systematically summarizes the functions and mechanisms of E3 ligases in DNA damage response and cancer therapy resistance, and further highlight recent advances in therapeutic approaches by targeting specific E3 ligases. Notably, combining E3 inhibitors with existing anticancer therapies may substantially enhance treatment responses and improve patient prognosis, providing a solid theoretical basis for future clinical applications.
Teng Ma, Yong-Zhu Zhou, Xiao-Jun Li et al.· Frontiers in Oncology· 0 citations
Cancer remains one of the leading causes of mortality worldwide, with
conventional therapies often limited by systemic toxicity, therapeutic resistance, and tumor heterogeneity.
Multi-target drug discovery has emerged as a contemporary strategy to overcome
these challenges, particularly through multi-kinase inhibitors and bispecific antibodies that simultaneously
modulate multiple oncogenic pathways.
This review integrates evidence from preclinical investigations, pivotal clinical trials,
regulatory approvals, and key patent literature underpinning the development of multi-target
anticancer agents. Representative multi-kinase inhibitors-including sorafenib, sunitinib, lenvatinib,
cabozantinib, and regorafenib-are critically analyzed with respect to their molecular
targets, therapeutic advantages, clinical performance, and associated intellectual property. Patented
innovations covering kinase inhibition platforms, antibody engineering, and biomarkerbased
cancer detection are also discussed.
MKIs act by concurrently inhibiting multiple signaling kinases, such as vascular
endothelial growth factor receptors, platelet-derived growth factor receptors, fibroblast
growth factor receptors, mesenchymal-epithelial transition factor, rearranged during
transfection, and rapidly accelerated fibrosarcoma, thereby suppressing angiogenesis,
limiting compensatory signaling, and addressing tumor heterogeneity. Clinical trials
demonstrate significant survival benefits in hepatocellular carcinoma, renal cell carcinoma,
and thyroid cancer. Parallel advances in patented bispecific antibodies and epigenetic
diagnostic technologies further expand the therapeutic and diagnostic landscape.
Multi-targeting strategies delay resistance, reshape the tumor microenvironment,
and improve outcomes, particularly when combined with immunotherapies or chemotherapies.
However, challenges persist, including off-target toxicity, pharmacokinetic variability, high
development costs, and limited accessibility. Patent trends reveal a growing emphasis
on biomarker-guided patient selection, novel antibody formats, and rational combination
therapies.
MKIs and bispecific antibodies represent transformative modalities in modern oncology,
supported by robust clinical evidence and extensive patent activity.
Thirumalaikumaran Rathinam, S. Pradeep Kumar Reddy, Yella Sirisha et al.· Recent Patents on Anti-Cance...· 0 citations