The Department of Chemical and Systems Biology Presents

Tarun Kapoor, Ph.D.
The Pels Family Professor
Head of the Selma and Lawrence Ruben
Laboratory of Chemistry and Cell Biology,
The Rockefeller University

Talk Title:  “Chemical biology of drug resistance”

Abstract: I will discuss how the analysis of resistance, which is generally considered to be a limitation of molecularly targeted therapeutics, can be leveraged to address major challenges in chemical biology. First, characterizing chemotype-specific resistance can help deconvolve a chemical inhibitor’s mechanism of action in human cells and achieve ‘gold standard’ validation of its direct target, i.e. when a silent mutation in the target suppresses drug activity in cell-based and biochemical assays. Second, examining resistance can help with the use of chemical inhibitors as probes of cellular mechanisms. In particular, phenotypes due to target inhibition can be identified as those observed in wildtype cells, across a range of inhibitor concentrations, but not in matched cells with a silent resistant-conferring mutation in the target. Finally, I will highlight our recent efforts to design new chemical inhibitors for AAA+ (ATPases associated with diverse cellular activities) proteins. Our approach, named RADD (Resistance Analysis During Design), involves testing selected chemical scaffolds against constructs with engineered silent mutations. Identifying mutations that confer resistance lead to robust inhibitor-target binding models that guide improvements in inhibitor potency and selectivity. These data can also help develop chemical strategies to overcome or delay the emergence of resistance.

Reading Material:

2. Cupido, T., Pisa, R., Kelley, M.E. et al. Designing a chemical inhibitor for the AAA protein spastin using active site mutations.
   Nat Chem Biol 15, 444–452 (2019). https://doi.org/10.1038/s41589-019-0225-6
3. Cupido, T., Jones, N.H., Grasso, M.J. et al.A chemical genetics approach to examine the functions of AAA proteins.
   Nat Struct Mol Biol 28, 388–397 (2021). https://doi.org/10.1038/s41594-021-00575-9

COVID guidelines:

• Attendees must complete the Health Check daily health attestation and COVID-19 testing requirements, where applicable.
• Attendees must follow all face covering requirements. It is recommended to wear face covering outdoors in crowded settings when six feet of distance cannot be maintained. You can lower face mask covering to eat and drink.
• We will have a sign-in sheet (for the purposes of contract tracing if needed.)

Please contact Yolanda Cervantes @ ycervant@stanford.edu for zoom details.