Next-Generation Anti-Cancer Drugs Using PROTACs and Targeted Protein Degradation

Drug resistance continues to limit the long-term benefit of many targeted therapies and chemotherapies against cancer. While “classical” small-molecule drugs excel at inhibiting enzymatic active sites, a large fraction of cancer-relevant proteins lack obvious pockets and are often labeled “undruggable.” In parallel, even well-druggable targets can become refractory through mutation, pathway rewiring, or compensatory signaling. These challenges drive the need for modalities that can eliminate disease-driving proteins rather than merely suppress their activity.Proteolysis-targeting chimeras (PROTACs) and related targeted protein degradation (TPD) approaches offer a distinct therapeutic logic: event-driven pharmacology. Over the past decade, advances in ligand discovery, linker design, structural biology, and proteomics have accelerated the translation of PROTAC concepts toward oncology pipelines. Yet major scientific and translational questions remain, such as selecting the right degrader mechanism for the right cancer context, optimizing tissue distribution and oral bioavailability, anticipating resistance routes, and defining fit-for-purpose pharmacodynamic biomarkers and regulatory-grade assays.This Research Topic aims to consolidate and advance the rapidly evolving field of PROTACs as next-generation anti-cancer therapeutics. By integrating innovations from medicinal chemistry, chemical biology, translational oncology, and drug development sciences, the collection will explore how targeted protein degradation can address unmet needs in cancer treatment. It specifically seeks to deepen understanding of degrader design principles, expand the toolbox of ligases and degradation modalities, strengthen translational strategies (biomarkers, PK/PD, patient selection), and highlight practical paths to clinical success, including combination regimens and approaches to overcome resistance.We accept a wide range of article types, including original research, reviews, mini reviews, methods, perspectives, systematic reviews. To gather further insights into PROTAC-enabled anti-cancer drug discovery, we welcome articles addressing, but not limited to, the following themes:o Degrader design and modalities covering PROTAC optimization plus molecular glues and other degradation routeso E3 ligase biology and selection including new ligases and tumor-context ligase choiceo Translation to clinic spanning PK/PD, target engagement, biomarkers, and patient stratificationo Resistance and combination strategies addressing heterogeneity, resistance mechanisms, and rational combinationso Safety and developability focusing on off-target/on-target risks, bioanalytics, CMC, and regulatory considerationso Computational progress in PROTAC design, modeling, and evaluationContributions from diverse research settings are encouraged to ensure balanced perspectives, from foundational chemical biology through first-in-human learnings, and to promote broadly applicable strategies for developing PROTACs and related degraders into safe, effective anti-cancer medicines. Topic editors: Mark Thomas Shaw Williams, Abdel Kareem Azab, Shang Su Source: https://www.frontiersin.org/research-topics/77444/next-generation-anti-cancer-drugs-using-protacs-and-targeted-protein-degradation