סמינר בכימיה אורגנית: New applications for Covalent Proximity Induction

Abstract:

Covalent inhibitors offer durable target engagement and high potency, but covalent bond formation is typically viewed as the endpoint of their function. We have developed Covalent Ligand Directed Release (CoLDR) chemistry, in which covalent engagement is coupled to release of the recognition element, enabling installation of functional groups on proteins while minimizing occupancy of the target binding site. This chemistry provides a modular strategy for protein labeling and, more broadly, for manipulating protein function through chemically induced proximity.

Here, we describe three applications of Covalent Induced Proximity. First, we describe PINCHs, a new pharmacological modality to induce protein precipitation in cells of homomeric proteins, that is differentiated from preivous modalities such as PROTACs. 

Second, we use bifunctional CoLDR-based recruiters to pharmacologically induce protein homodimerization. Using BTK as a model system, we identify an intrinsic self-inhibition mechanism arising from the CoLDR reaction and show how ligand properties can be tuned to overcome it. Extending this approach to KRAS G12C enables robust covalent dimer formation in cells. Remarkably, low levels of induced KRAS G12C dimerization are sufficient to activate ERK signaling and increase cellular viability, providing a chemical approach for interrogating the functional consequences of protein dimerization.

Third, we exploit template-assisted CoLDR reactions to develop a modular “Trojan horse” strategy for targeted protein degradation. In this approach, binding to a cellular protein creates a template for covalent installation of a recruiter, generating the functional degrader in situ. Using BRD4 as an initial template, we demonstrate degradation of multiple targets, including the estrogen receptor, androgen receptor, and BCL6. The resulting degraders show potent and selective cellular activity and provide a potential route to recruit ubiquitin ligases and other effectors that lack conventional ligandable binding pockets.

Together, these studies expand CoLDR chemistry from a protein-labeling strategy into a versatile platform for controlling protein–protein interactions and cellular signaling. By separating initial molecular recognition from the functionality ultimately installed on a protein, CoLDR provides new opportunities for proximity-based chemical biology and targeted protein modulation.