Therapeutic Inhibition of MYC:TRRAP Interaction in Cancer

PROJECT SUMMARY The long-term product goal of this project is a small molecule cancer therapeutic targeting the MYC oncoprotein, which is a transcriptional factor that regulates key transcriptional programs required for cellular growth and proliferation. Due to its aberrant expression in more than 70% of human cancers and the functional validation that MYC inhibition arrests cancer growth, MYC has been the most sought-after therapeutic target in cancer. Despite decades of effort, therapeutic targeting of MYC has been unattainable due to a combination of factors, including a lack of enzymatic activity or obvious ligand binding sites that can aid in inhibitor identification. Recent research by the PI, Dr. Feris, in the Cole laboratory at Dartmouth, has uncovered an Achilles’ heel in MYC that has enabled therapeutic targeting of this previously undruggable target. While unraveling the molecular mechanism underlying MYC’s interaction with the TRansactivation/tRansformation-domain Associated Protein (TRRAP), which is essential for many of the MYC-driven aberrant transcriptional programs that promote cancer, Dr. Feris’ research revealed a vulnerability in MYC. This insight led to the development of a revolutionary screening platform which was later deployed to screen more than 0.5 million compounds. Partial assessment of the high-throughput screening (HTS) efforts identified several hits that not only blocked intracellular MYC:TRRAP protein-protein interaction (PPI) at low µM potency but also potently (2 µM) attenuated 2D and 3D growth of multiple cancer cell lines in a highly MYC-dependent manner, highlighting the specificity and selectivity of the hits. The goal of the current Fast-Track application is hit-to-lead development of these and any additional new hits for future clinical development as novel MYC-targeted therapeutics for cancer. The focus of the one-year Phase I STTR portion of the Fast-Track project is to conclude hit discovery efforts by completing HTS hit assessment while simultaneously testing the hypothesis, using our recently-identified heterocyclic amide compound (A1), that MYC:TRRAP PPI inhibition attenuates tumor growth in a human lymphoma xenograft model. The focus of the two-year Phase II SBIR portion of the Fast-Track project is hit-to-lead generation of advanced leads using an iterative process combining medicinal chemistry, in vitro MYC-specific bioassays, in vitro ADME/ tox, PK and efficacy in the mouse human lymphoma model. Identification of at least one safe and efficacious advanced lead compound that reduces tumor burden by >50% would constitute study success. Given the ubiquity of MYC-driven cancers, a MYC-targeted therapy, which is currently lacking, would be of immense therapeutic value to cancer patients. This Fast-Track application will enable completion of foundational studies, which are currently undertaken by cosMYC, Inc, a biotech company co-founded by Dr. Feris to drive the product towards commercialization. Moreover, this ‘Small Business Transition Grant for Early Career Scientists’ will enable the successful transitioning of Dr. Feris from an academic scientist to an industry executive to oversee business development activities that are critical to ensure that this transformative therapy reaches patients.