In this project, we propose to develop new small molecule MYC inhibitors (MYCi) for targeting c-MYC/N-MYC in prostate cancer and as tools to sensitize prostate tumors to ICB therapy. The series of MYC inhibitors we have developed thus far are highly drug-like and have shown excellent pharmacokinetic, toxicological and anti-tumor activity profiles in MYC-driven models of prostate cancer and leukemia. The compounds engage MYC inside cells as shown by the cellular thermal shift assay (CETSA); disrupt MYC/MAX complex formation which is required for MYC activity; and inhibit MYC-driven target gene expression. Furthermore, the MYCi compounds enhance phosphorylation of MYC on threonine-58 (T58P) which promotes MYC degradation via the ubiquitin-proteasome pathway. Consequently, treatment with MYCi reduced tumor cell proliferation and tumorigenicity in vitro and in vivo. Treatment of prostate tumor-bearing immunocompetent mice with MYCi led to increased tumor infiltration by T cells, B cells and NK cells as well as robust induction of PD-L1 immune checkpoint protein expression on tumor cells. These observations suggest that MYCi may sensitize otherwise refractory tumors to anti-PD1/PD-L1 immune checkpoint blockade therapy. Indeed, preliminary studies indicate synergy between MYCi and anti-PD1 antibody therapy. The goals of this project are to develop MYCi for clinical application through lead optimization in preparation for IND filing and to characterize the mechanisms of MYCi action and synergy with ICB immunotherapy.
|Effective start/end date||10/23/19 → 10/22/22|
- Prostate Cancer Foundation (19CHAL06)
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