Gene fusions involving NTRK1, NTRK2 or NTRK3 (encoding the tropomysin receptor kinases TRKA, TRKB and TRKC) are well-established oncogenic drivers present in a wide range of adult and pediatric tumor types. Treatment with approved, first-generation TRK inhibitors larotrectinib and entrectinib have led to high response rates in patients who harbor these fusion proteins. Invariably, resistance occurs which results in kinase domain mutations that prevent inhibitor binding leading to tumor progression. Thus, there is a need for efficacious and selective inhibitors that can overcome these resistance mutations, which could lead to more durable responses for a greater number of patients. In contrast with other second generation NTRK inhibitor programs, BLU-847 was designed to specifically target wild-type TRK proteins with equipotent activity against the challenging solvent front mutations NTRK1(G595R), NTRK2(G639R), NTRK3(G623R) while maintaining exquisite kinome selectivity. We will describe the discovery of BLU-847 which utilized structure-based drug design and structure-activity relationships (SAR) to optimize overall drug properties. BLU-847 demonstrated pharmacological activity in mouse xenograft models with both wild-type and solvent-front mutations and was well-tolerated preclinically with a low projected human dose.

Discovery of BLU-847: Potent, highly selective inhibitor of the tropomysin receptor kinases TRKA, TRKB and TRKC, with in vivo activity against key clinical resistance mutations

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.