From Degraders to Modulators: Advances in Proteolysis Targeting Chimeras and Novel Targeted Therapies

The area of targeted protein modulation is undergoing rapid evolution due to breakthroughs in chemical biology and proteome engineering. Initially spearheaded by the development of PROTACs (Proteolysis Targeting Chimeras), which utilize the ubiquitin-proteasome pathway to eliminate disease-driving proteins, the field has now expanded into fine-tuned protein modulation. With PROTACs making previously “undruggable” targets accessible and several candidates, such as ARV-110 and ARV-471, progressing through clinical trials, attention is shifting toward emerging strategies that go beyond protein degradation. These include stabilization, conditional modulation, and the use of bifunctional molecules that influence post-translational modification and non-ubiquitin-based elimination, thus reconceptualizing how cellular function and protein homeostasis are understood in health and disease. Although progress has been substantial, fundamental questions remain regarding optimal molecular design, comprehensive mechanistic insight, and streamlined clinical translation to unlock the full clinical potential of these innovative modalities.This Research Topic aims to delineate and foster discussion on the burgeoning landscape of protein-targeting modalities, uniting contributions from chemical biology, cell biology, and medicinal chemistry. Through a cross-disciplinary lens, the aim is to address the evolving questions around target and E3 ligase discovery, design principles for bifunctional and molecular glue molecules, alternative mechanisms such as autophagy and lysosomal degradation, and the translation of these technologies into disease contexts. Of central interest are recent discoveries that both extend the mechanistic boundaries of protein modulation and offer new opportunities for the intervention in diverse disease settings—from cancer to neurodegeneration and beyond. The objective is to shine light on unanswered scientific questions, approaches for rational drug design, and strategies to accelerate the adoption of these approaches into the clinic.The scope of this Research Topic focuses on developments and applications in targeted protein degradation as well as emerging precision modulators, while excluding conventional small molecule inhibitors or unrelated therapeutic strategies. To gather further insights in this rapidly developing research area, we welcome articles addressing, but not limited to, the following themes:o Discovery and engineering of novel E3 ligases and molecular partners in PROTAC development.o Rational design, linker optimization, and structure-activity relationship studies for emerging bifunctional molecules.o Novel mechanisms and technologies for protein stabilization, post-translational modification, and beyond degradation (e.g., DUBTACs, PhosTACs, AUTOTACs, LYTACs, GlueTACs).o Applications of protein-targeting chimeras in model systems to study cellular dynamics, cell fate, and disease phenotypes.o Preclinical and clinical translation: pharmacokinetics, safety, efficacy, and expansion to new therapeutic areas. Topic editors: Zengtao Wang, Xing Liu, Aimei Liao, Seth Shatkin Margolis Source: https://www.frontiersin.org/research-topics/82702/from-degraders-to-modulators-advances-in-proteolysis-targeting-chimeras-and-novel-targeted-therapies