Prof. Michelle Arkin
University of California, San Francisco
https://www.linkedin.com/in/michelle-arkin-046393/
Biography
Michelle Arkin is a chemical biologist, Professor and Chair of Pharmaceutical Chemistry, and Executive Director of the Small Molecule Discovery Center (SMDC) at UCSF. Michelle’s research focuses on developing methods and molecules that target currently ‘undruggable proteins,’ including protein-protein interactions and dynamic or intrinsically disordered proteins. She is a cofounder and Director of Ambagon Therapeutics, cofounder of Elgia Therapeutics, and advisor to several biotechs. Prior to UCSF, Michelle was Associate Director of Cell Biology at Sunesis Pharmaceuticals, where she helped discover inhibitors of protein-protein interactions for IL-2/IL-2R and LFA1/ICAM (lifitegrast, marketed by Novartis). She earned her PhD in Chemistry at Caltech and held a Damon Runyon postdoctoral fellowship at Genentech.
Presenting
Keynote Speaker
Closing Keynote: Prospective discovery of molecular glues using site-directed fragments
Molecular glues (MGs) – compounds that induce or stabilize protein-protein interactions – are fundamentally changing the way drug hunters think about targeting previously undruggable targets. Natural and synthetic MGs can induce non-native (neomorphic) interactions or further stabilize native complexes; they can also lead to pathway activation, inhibition, or even degradation of one of the target proteins. Creative cellular approaches have been developed to screen for MGs, particularly MG degraders. Nevertheless, there are few methods for prospective discovery of MGs for a particular protein-protein interaction. Our collaborative team has developed cell-active molecular glues for several proteins, including the kinase CRAF and transcription factors estrogen receptor and YAP, that bind to the phosphoprotein-chaperone 14-3-3. Our approach to systematic discovery of MGs uses the disulfide tethering and other reversible covalent libraries to screen for fragments that bind to the protein complex more strongly than to either of the individual proteins. By increasing residence time, covalency might increase the chance for both proteins and compound to form a ternary complex. Through screening and structure-guided optimization, we are developing the rules-of-thumb for designing molecular glues.