Development of a novel MYC inhibitor for cancer therapy

Summary MYC proteins (including c-MYC, N-MYC and L-MYC) are critical oncogenic drivers that regulate multiple cancer hallmarks. The evidence indicating that MYC is a critical oncogenic driver that regulates multiple cancer hallmarks is compelling. Recent pan-cancer analyses of over 9,000 human cancers of various types found amplification of MYC genes in ~28% of all cases. In addition, multiple mechanisms exist in tumor cells that frequently lead to the upregulation of MYC mRNA and protein expression, leading to estimates that MYC proteins are involved in at least 70% of all human cancers. MYC is particularly important in many therapy-resistant cancers. For example, in castration-resistant prostate cancer (CRPC), c-MYC is amplified in 45% of cases, while in late-stage neuroendocrine prostate cancer (NEPC), N-MYC is overexpressed in 40% of cases. In non-small cell lung cancer, MYC promotes resistance to targeted therapies against EGFR and ALK. In hepatocellular carcinoma (HCC), c-MYC protein is overexpressed in up to 70% of cases across all stages and grades, implicating MYC as a prevalent, early and critical event in tumorigenesis. Thus, inhibiting MYC systemically with a small molecule MYC inhibitor may lead to profound antitumor activity across many cancer types. However, to- date, no small molecule MYC inhibitor has been developed into the clinic. To address this drug target, we set out to develop small molecule MYC inhibitors suitable for development as a new therapeutic for cancer. After implementing a novel in silico screen, novel in vivo testing, extensive medicinal chemistry optimization, and thorough in vitro and in vivo characterization, we developed a novel series of direct small molecule MYC inhibitors that demonstrate profound antitumor efficacy in MYC-driven models of prostate, liver, and other tumor types. Our lead compound, MYCi606, completely eliminates HCC tumors in multiple syngeneic models and induces immunological memory in HCC, suggesting this compound has the potential to be an extremely impactful new therapeutic for liver cancer. Vortex Therapeutics has initiated IND-enabling studies on MYCi606. In this proposal, we seek funding to continue this the development of MYCi606 by completing process development and GLP toxicology studies. These efforts will position us for filing an IND in the near-term to study the first direct MYC inhibitor in human clinical trials. Project Number: 1R44CA302283-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Ben Vollrath | Institution: VORTEX THERAPEUTICS INC, LOMBARD, IL | Award Amount: $1,102,729 | Activity Code: R44 | Study Section: Special Emphasis Panel[ZCA1 SRB-5 (M2)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11256033