In cancer, epigenetic proteins are among the most promising and intently pursued targets in drug discovery. This relates to the growing appreciation that cancer growth pathways are centrally influenced by proteins that modify chromatin. Already, inhibitors of DNA methyltransferases and histone deacetylases have demonstrated substantial clinical efficacy, leading to regulatory approval for use in hematologic malignancies. These events have triggered intense competition to develop inhibitors of the chromatin-modifying enzymes known as epigenetic “writers” and “erasers.” Perhaps owing to perceptions regarding the feasibility of targeting protein-protein interactions, small-molecule inhibitors of chromatin-binding modules or epigenetic “readers” have received considerably less attention. Recently, we reported the first potent small-molecule inhibitor of human bromodomains, JQ1, which exhibits selectivity for the BET family of bromodomain-containing transcriptional coactivators. Of broad relevance to cancer, we demonstrated that c-Myc expression is critically dependent on BRD4 function and localization to discrete upstream regulatory regions. Exposure of cancer cells to JQ1 prompts immediate downregulation of c-Myc expression, leading to suppression of a transcriptional program associated with proliferation, survival, and metabolic adaptation. In translational models of MYC-dependent hematologic malignancies, in particular multiple myeloma, the efficacy of JQ1 treatment establishes a mechanistic rationale for the leveraged clinical development of drug-like JQ1 derivatives. Toward this objective, we have completed chemical optimization of novel, drug-like inhibitors of BET bromodomains as reagents capable of supporting human clinical investigation. This research has established the feasibility of inhibiting epigenetic reader proteins with efficient, cell-permeable small molecules. In addition, we have developed a high-throughput platform for modeling mechanism-based, drug-drug combinations to achieve synergy in translational model systems of multiple myeloma. In support of an open-innovation model of chemical biology, we have created a chemical probe allowing the broad study of chromatin biology, which has already been provided to more than 350 academic, governmental, and industrial laboratories worldwide. Together, we have rapidly identified mechanism-based opportunities for clinical translation in cancer.
Bradner:SHAPE Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Acetylon Pharmaceuticals: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Tensha Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.