Optimization Leading to a Potent and Selective Cbl‑b Inactive-State Inhibitor That Demonstrated In Vivo Efficacy

In the preceding work in this issue (10.1021/acsmedchemlett.6c00103), we described our initial structure-activity relationship (SAR) optimization that led to a pan-Cbl inhibitor (6) that demonstrated efficacy in a mouse CT26 syngeneic model. Unfortunately, attempts to improve TGI with higher doses of 6 resulted in poor tolerability which we attributed to a lack of selectivity between Cbl-b and c-Cbl (∼2× by surface plasmon resonance (SPR)). Herein, we report our continued efforts that led to a breakthrough in achieving Cbl-b selectivity (up to 37×). The lead compound 33 demonstrated 14× selectivity against c-Cbl by SPR, was potent in a PBMC cell assay, and showed good oral exposure in mice. When tested in a CT26 model, 33 displayed improved tumor growth inhibition compared to our previously reported pan-Cbl inhibitor 6 (TGI 145% vs 82%). More importantly, 33 was better tolerated than 6, supporting our hypothesis that a selective Cbl-b inhibitor could be advantageous relative to a pan-Cbl inhibitor.