Small Molecule MYC Degraders as Novel Cancer Therapeutic Agents

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PROJECT SUMMARY/ABSTRACT The MYC family proteins are comprised of three paralogs termed c-myc, N-myc, and L-myc. The MYC proteins play a fundamental role in cell proliferation and oncogenesis by regulating cellular processes such as gene transcription, protein translation, cell cycle progression, and cell death. While N-myc and L-myc drive oncogenesis in a small number of cancer types, the requirement of c-myc is widespread in a broad range of human cancers. MYC protein levels are highly regulated by Aurora A: both c-myc and N-myc bind to Aurora kinase A to “escape” proteasomal degradation. With the support of SBIR Phase I, we have successfully identified novel small molecules that 1). directly target the MYC:Aurora A binding interface, 2). potently degrade both endogenous N-myc and c-myc (henceforth “MYC degraders”), 3). are metabolically stable and orally bioavailable, and 4). are efficacious in inhibiting the growth of tumors dependent on either N-myc or c-myc. For the SBIR Phase II period, we plan to advance pre-clinical development of our MYC degraders with an emphasis on treating c-myc-dependent cancers. We propose two specific aims: Specific Aim 1: Test the efficacy of SSTA-315 across c-myc dependent cancers, while in parallel develop derivative c-myc degraders with improved potency and efficacy. Specific Aim 2: Evaluate the safety profile of SSTA-315 (or an alternative lead MYC degrader) in IND-enabling GLP toxicity studies. Successful completion of the proposed studies will complete IND-enabling safety studies for our lead MYC degrader, preparing for the IND registration with the FDA as the immediate next step. Given that MYC proteins are deregulated in most human cancers, our MYC degraders have potential to impact the lives of millions of cancer patients in U.S. and represent a significant market opportunity.