Chemical Probe Discovery for Ligases that Govern MYC Post-Translational Stability


Angela Koehler, PhD, Massachusetts Institute of Technology

The transcription factor Myc is a master regulator that controls the expression of about 15% of all genes. It responds to many signal transduction pathways including the Wnt pathway and the MAPK cascade. Deregulation of Myc-mediated transcription can lead to tumorigenesis by activating cellular growth, proliferation, self-renewal, and evasion of apoptosis. As such, a longstanding goal of the cancer research community has been to find ways to directly target Myc. Despite these efforts, this aim has proven extremely challenging, as Myc lacks a classically “druggable” binding pocket. However, recent technologies harnessing the ubiquitin-proteasome system (UPS) may expand options for targeting Myc. E3 ubiquitin ligases are critical in the regulation of protein homeostasis and have been successfully recruited to induce controlled proteasome-mediated degradation of cancer targets using heterobifunctional proteolysis-targeting chimera molecules (PROTACs).

In this project, Angela Koehler of the Massachusetts Institute of Technology and her team are carrying out small-molecule microarray binding screens for Myc as well as E3 ubiquitin ligases that they have implicated in Myc protein degradation, including HUWE1 and FBXW7. They are working to expand the repertoire of targeting ligands for PROTAC development and to build tools that can assess the potential of selectively degrading Myc. Molecules that directly bind E3 ligases may modulate their functions or serve as starting points for the development of new molecular glues. The team is also assembling a set of complementary assays to serve as a critical path for chemical probe development. This work emphasizes the development of ligand-binding assays, but future goals of the team include preliminary functional assessment of the molecules and evaluation of their potential within PROTACs aimed at MYC, MYB, and CDK9, among other targets.

Angela Koehler, PhD