Frontiers in Chemistry and Chemical Engineering
Brian Liau is an associate professor in the Department of Chemistry and Chemical Biology at Harvard University. He obtained his bachelor’s degree in Chemistry and Physics from Harvard College, before receiving a PhD in Chemistry under the guidance of Dr. Matthew Shair. During his PhD studies, Brian completed the chemical synthesis of complex bioactive natural products and investigated their biological mechanism of action. As a postdoctoral fellow with Dr. Bradley Bernstein at Massachusetts General Hospital, he studied epigenetic mechanisms of adaptation and drug resistance in brain cancer. In 2016, Brian started his independent research group, which integrates chemical biology with genomics to unravel chromatin complexes and gene regulation. The Liau lab has pioneered chemical genomic approaches to systematically identify drug resistance-conferring mutations for protein drug targets, which they leverage in mechanistic studies to discover small molecule mechanism of action and new target biology.
The orchestrated interactions of protein complexes control cell function and state. Dysregulation of these interactions can underlie human disease, and therapeutic approaches to modulate them by blocking or even creating interactions with small molecules are transforming paradigms for drug discovery. Beyond their promise as therapeutics, small molecules are powerful tools to dissect the function and biology of protein complexes, yet their full potential is only unlocked if we understand their mechanisms of action. By combining genome editing with small molecule profiling, we describe the systematic identification of drug resistance-conferring mutations across protein targets of interest. These drug resistance mutations not only confirm on-target engagement but can be leveraged as discovery tools to uncover new phenomena. In this seminar, I will showcase these capabilities through two vignettes elucidating small molecules targeting the LSD1 corepressor complex. I will describe how the application of our chemical genomic approaches enabled us to deconvolute drug mechanism of action and reveal a remarkable mechanistic convergence between a molecular glue degrader and cancer mutations, reshaping our views on targeting protein-protein interactions for therapeutic applications and targeted protein degradation.
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