Ripretinib

Ripretinib is an inhibitor of KIT and PDGFRα (IC₅₀s = 3 and 3.6 nM, respectively).¹ It is selective for KIT and PDGFRα over a panel of 300 kinases (IC₅₀s = >100 nM) but does inhibit DDR2, VEGFR2, PDGFRβ, and Tie2 (IC₅₀s = <10 nM for all). It also inhibits mutant isoforms of KIT and PDGFRα, including KIT^V654A, KIT^T670I, KIT^D816H, KIT^D816V, and PDGFRα^D842V (IC₅₀s = 11, 9.2, 18, 25, and 36 nM, respectively). Ripretinib induces apoptosis in ROSA wild-type, and KIT^D816V- or KITK^509I-expressing mast cells in a concentration-dependent manner.² It reduces tumor growth and increases survival in an imatinib-resistant patient-derived xenograft (PDX) mouse model of gastrointestinal stromal tumors (GISTs) when administered at doses of 50 and 100 mg/kg.¹ Formulations containing ripretinib have been used in the treatment of GISTs.

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1. Smith, B.D., Kaufman, M.D., Lu, W.-P., et al. Ripretinib (DCC-2618) is a switch control kinase inhibitor of a broad spectrum of oncogenic and drug-resistant KIT and PDGFRA variants. Cancer Cell 35(5), 738-751 (2019).

2. Schneeweiss, M., Peter, B., Bibi, S., et al. The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis. Haematologica 103(5), 799-809 (2018).