New applications for Covalent Ligand Directed Release chemistry

Covalent Ligand Directed Release (CoLDR) chemistry has emerged as a versatile strategy for targeted covalent modulation of protein function. In this talk, I will present several new (unpublished) applications of CoLDR chemistry spanning molecular optimization, targeted protein degradation, and protein activation. I will describe the development of high-throughput synthetic approaches for rapid generation and optimization of CoLDR inhibitor libraries. I will then present a high-throughput screening platform for the discovery of novel CoLDR-based PROTACs and will discuss the design and evaluation of new DCAF16-recruiting CoLDR PROTACs for targeted protein degradation. Finally, I will demonstrate how homodimeric CoLDR recruiters can be leveraged for induced protein activation, highlighting an emerging application of CoLDR chemistry beyond degradation. Together, these studies establish CoLDR as a broadly applicable platform for chemical biology and therapeutic discovery.