Recent insight into the mechanisms of chromatin-modifying complexes in cancer has led to the development and FDA approval of small molecules that target these mechanisms. Much of the initial chromatin-directed drug discovery has focused on complexes that methylate histones (EZH2 and Menin/KMT2A). However, there is increasing interest in small-molecule discovery targeting complexes that acetylate histones. Efforts targeting CBP/P300, ENL, and KAT6A have shown early clinical or pre-clinical success, validating the importance of histone acetylation in maintaining oncogenic programs in AML and solid tumors. AML remains essentially an incurable disease in adults (and ~60% cure rate in children/adolescents) even though there has been some recent progress in drug development, including the approval of Venetoclax and of Menin:KMT2A inhibitors. However, resistance develops to both drugs, presenting a need for orthogonal pharmacologic approaches to targeting the core transcriptional programs of this disease.
Investigators Eric Fischer and Scott Armstrong are developing a small-molecule degrader for a novel chromatin-modifying target important for maintaining oncogenic programs in AML and other diseases. They have developed advanced tool compounds demonstrating early in vivo efficacy and will, in the course of this drug discovery award, conduct a lead optimization campaign. By the end of the project, they expect to have identified potent and selective molecular glues that have excellent drug-like properties and defined a clinical path for further development.