生命科学联合中心

学术报告

Title：Leveraging resistance for chemical inhibitor design, validation and use

Speaker： TARUN M. KAPOOR, Ph.D.

The Pels Family Professor

Head of the Selma and Lawrence Ruben Laboratory of Chemistry and Cell Biology

The Rockefeller University

Time：2018-3-1（周四），13:00 -14:00 pm

Venue：北京大学化学与分子工程学院A204报告厅

Host：王初，北大-清华生命科学联合中心

I will discuss how 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, analysis of chemotype-specific resistance can 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, 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, resistance analyses can be used to design chemical inhibitors. I will highlight our recent efforts to design new inhibitors for AAA+ (ATPases associated with diverse cellular activities) proteins. Our approach involves testing selected chemical scaffolds against constructs with engineered silent mutations. These data yield a robust model that guides improvements in inhibitor potency and selectivity. This approach leads to spastazoline, an inhibitor of the microtubule-severing AAA+ protein spastin.