QBI - Seminar

Merging Functional Genomics and Drug Design: IFITM Proteins and Linked Chemotypes

QBI presents a seminar with Kevin Lou, a MD/PhD student at UCSF. His work investigates the structural features of therapeutic molecules important in mediating drug-cell interactions using an approach that combines functional genomics and drug design. He conducted graduate studies in the lab of Kevan Shokat and in close collaboration with Luke Gilbert.

Increasingly, it has been found that certain linked molecules, chemical entities composed of multiple ligands linked together (e.g. PROTACs and others), outside traditional small molecule design frameworks can maintain drug-like properties despite their large size and flexibility while gaining new mechanisms of action. Using functional genomics, Kevin and his group identified IFITM-assisted cellular uptake as a general mechanism by which such molecules can gain access to the cytosol, motivating the design of compounds with longer linkers than typically explored. Among the therapeutic modalities most enabled by these longer linker lengths are bitopics, molecules that simultaneously engage two sites on a single target. They have developed an optimization process for the design of bitopic inhibitors beyond the prototype molecule RapaLink-1. This is exemplified by our lead bitopic BCR-ABL inhibitor PonatiLink-2, which exhibits greater selectivity than current clinical compounds and potently inhibits certain highly resistant active-site mutants. In future work, they aim to generalize bitopic inhibitors to other targets, and to explore functional genomics and chemical-genetic interactions as a means for discovery of new chemical mechanisms of action.

Talk Title: Merging Functional Genomics and Drug Design: IFITM Proteins and Linked Chemotypes

Host: Nevan Krogan

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