molecules of the month

compound 10

tumor specific prodrug of TGFβR inhibitor

QW dosing, improved tumor-to-heart ratio

BMS-986260 prodrug w/ self-immolative link.

Journal of Medicinal Chemistry

Bristol Myers Squibb, Princeton, NJ

Chemical structure of "compound 10" BMS TGFβR inhibitor prodrug
1 min read

The BMS TGFβR inhibitor prodrug, “compound 10,” demonstrates antitumor efficacy comparable to the parent compound (BMS-986260) in a syngeneic model with once-weekly dosing, while reducing the systemic exposure of BMS-986260. Reducing the systemic exposure of a TGFβR inhibitor is important due to previously observed mechanism-based cardiac toxicity. This prodrug is preferentially cleaved by proteases overexpressed in tumors, and results in a prolonged, favorable tumor-to-heart ratio of the active drug in distribution studies. This is an interesting proof-of-concept for tumor-targeted prodrugs as an approach to improving the therapeutic index of cancer drugs. It is especially interesting in the immune-oncology setting where the initiation of anticancer activity in a tumor may lead to an abscopal effect and broader systemic responses due to…

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