Therapeutic Inhibition of MYC:TRRAP Interaction in Cancer (I-Crops Supplement)

RESEARCH STRATEGY Executive Summary of Predicate SBIR or STTR Phase I Grant and Team cosMYC, Inc. intends to develop and commercialize small molecule cancer therapeutics that selectively target the MYC oncoprotein, which is a transcriptional factor that regulates key transcriptional programs required for

cellular growth and proliferation. Due to its overexpression in more than 70% of human cancers and the functional validation that MYC downregulation 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 (cosMYC CEO), 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 assay 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 specific aims of the one-year Phase I STTR project are to: (1) conclude hit discovery efforts by completing HTS hit assessment and (2) test the hypothesis, using our

recently identified heterocyclic amide compound (A1), that MYC:TRRAP PPI inhibition attenuates tumor growth in a human lymphoma xenograft mouse model. The goal of the future Phase II project is hit-to-lead development of Phase I hits for future clinical development as novel MYC-targeted therapeutics for cancer.

A. Cancer B. No Cancer Inhibitor TRRAP TRRAP MAX protein X MYCMYC Target genes Target genes Figure 1. Project Premise. Small-molecule inhibitors of MYC-TRRAP interaction can block MYC-driven aberrant transcriptional programs to prevent cancer. Ed Feris, PhD (C-level Corporate Officer, CLO): Dr. Feris is the program PI/PD and CEO of cosMYC. He has

significant training and research experience in the fields of molecular, cellular, and cancer biology, specifically pertaining to MYC. Dr. Feris’ expertise and experience in MYC biology and drug discovery make him ideally suited to lead these efforts. John F. Kaufmann, MBA (Technical Lead/Expert, TL): Mr. Kaufmann is a consultant at cosMYC, Inc. and has

served S1Biopharma Chief Financial Officer since April 2012. He has successfully completed the I-Crops program in the past and is an expert in late stage pre-clinical/early-stage clinical drug development. James R. Boyle (Industry Expert, IE): Mr. Boyle is a business development executive with significant

experience in transforming academic innovations into medicines through commercial enterprises. Currently, he is a limited partner in Good Growth Capital, an early-stage VC fund focused on climate tech, life sciences, and data sciences with $150MM AUM (2021-present). All three individuals are aware of and are committed to the time requirements of the NIH’s I-Corps program.