Small molecules MYC inhibitors that are efficacious and tolerated in vivo will provide invaluable chemical probes and potential therapeutic agents. We have used in silico screening coupled to a rapid in vivo screen in mice to develop a series of novel small molecule MYC inhibitors (MYCi) which engage MYC inside cells, disrupt MYC/MAX heterodimerization and inhibit MYC-regulated gene expression. The compounds enhanced MYC phosphorylation on threonine-58, leading to increased proteasome-mediated degradation of MYC. The initial lead, MYCi361, showed excellent in vivo anti-tumor efficacy in mice, inhibiting proliferation and inducing immunogenic cell death of tumor cells. MYCi361 treatment increased tumor infiltrating lymphocytes and induced tumor PD-L1 expression. Accordingly, treatment with MYCi361 sensitized tumors to anti-PD1 immunotherapy. MYCi361 however showed a narrow therapeutic index. We therefore undertook additional medicinal chemistry optimization, which yielded the related molecule, MYCi975, which combined in vivo efficacy with remarkable tolerability. These findings support the potential of small molecule MYC inhibitors as chemical probes and possible therapeutic leads.

Citation Format: Huiying Han, Atul Jain, Vinay Sargar, Jonathan Anker, Rama Mishra, Gary Schiltz, Sarki A. Abdulkadir. Development of small molecule MYC inhibitors that impair tumor growth and enhance anti-PD1 immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-273.