A general approach for the design of covalent protein proximity inducers

Chemical biology has made remarkable strides over recent decades, producing potent and selective inhibitors for many proteins, including essential drug targets. Despite these achievements, however, inhibition has been the primary mode of perturbation (GPCRs notwithstanding), whereas many biological processes are controlled through a rich spectrum of biochemical perturbations. What if a small molecule could activate an enzyme? Install or remove a post-translational modification (PTM)? Or control its oligomeric state?The overarching goal of this proposal is to dramatically increase the scope and breadth of perturbations and PTMs one can induce in cells using small molecules. Accomplishing this will have tremendous impact on the ability to investigate numerous cellular processes and holds massive therapeutic potential.To achieve this goal, we will build on our recently developed Covalent Ligand-Directed Release (CoLDR) chemistry, which allows totag proteins covalently while preserving their function. Our research will develop:1. a general method to create CoLDR-based probes against a panel of targets, that would enable us to harness their activity forselective perturbation of new, non-endogenous, substrates.2. homo-dimeric CoLDR probes to induce selective dimerization of targets. This will allow us to selectively activate targets such askinases in cells. We will also design protein polymerizers, by tethering obligatory homodimers.3. chimeric proximity inducers that would selectively modify new targets in vitro and in cells.Our group’s experience in covalent chemical biology, proteolysis-targeting chimeras, and the development of the CoLDR platform,makes us uniquely positioned to create the next generation of covalent proximity inducers.