Project leader: Mike Serrano-Wu, Ph.D.
Key collaborators: Todd Golub, M.D.; Guo Wei, Ph.D.
MCL1 is one of the most commonly altered genes in cancer. It is linked to tumor development across a wide variety of cancer types, and is strongly implicated in chemotherapy resistance. These findings suggest that MCL1 is a highly attractive therapeutic target in cancer.
To date, most MCL1 drug discovery efforts have focused on a specific region of MCL1 that binds to other proteins via the so-called BH3 helix. Researchers have searched for chemical compounds that can disrupt this interaction and form the basis of a candidate drug. However, their efforts have met with limited success, suggesting that the biology of the protein may be more complex than initially imagined – in particular, that there may be other proteins, as yet unknown, that interact with MCL1 and orchestrate its role in cancer.
To crack open this problem, Broad Institute scientists have used comprehensive approaches to identify more than 200 proteins that bind to MCL1. These binding partners, together with other innovative cell-based tools, serve as the critical groundwork in our systematic search for chemicals that can disrupt MCL1 function.