Degradation of cancer causing proteins
The number of biologically validated cancer drug targets far outnumbers the number of pharmacologically and clinically validated drug targets. A large reason for this disparity is that many cancer targets require modulation of protein•protein interactions typically considerable ‘undruggable.' To address this problem we identify novel targets and compounds that promote specific degradation of such targets. Proteins are tagged for degradation post-translationally by the addition of ubiquitin chains, which encode for proteosomal and lysosomal degradation. Addition and removal of ubiquitin tags on substrates are coordinated by the action of ubiquitin activating, conjugating, and ligating enzymes (E1, E2, E3) and deubiquitylating enzymes (DUB). A growing number of DUB family members have been shown to rescue oncoproteins from degradation using genetic methods however a lack of potent and selective small molecule inhibitors has hindered pharmacological and clinical validation of DUBs. DUBs are proteases, a class of enzymes for which clinical stage inhibitors of non-DUB members exist. The mission of our group is to develop first-in-class inhibitors and prototype drugs for DUBs that can be utilized to pharmacologically validate members of the gene family as new targets for cancer treatment and other diseases. Our approach is to: 1) Execute target, gene family and peptidomimetic approaches to achieve new DUB inhibitors; 2) Screen DUB inhibitor libraries for anti-cancer activities; and 3) Pursue validation and mechanistic work for selected DUBs and compounds. We are also committed to developing technologies that accelerate ubiquitin system and especially DUB research. To accomplish these goals we work as a collaborative team of synthetic chemists, biochemists, cell biologists and structural biologists.