KIN-8194 is an orally active dual inhibitor of HCK and BTK, with IC50 values of 0.915 and <0.495 nM, respectively. KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma (MCL). KIN-8194 overcomes ibrutinib resistance with a survival benefit in TMD-8 ABC DLBCL xenografted mice.
KIN-8194 (0-1 μM, 7 days) inhibits the growth of MCL cell lines (Maver-1, JeKo-1, Mino, Rec-1 and Granta-519) and primary cells[1].KIN-8194 (0-1 μM, 7 days) reduces MCL cell lines proliferation through HCK inhibition[1].KIN-8194 (100 nM, 6 h) inhibits the AKT-S6 signaling pathway in Maver-1 and Granta-519 cells in an HCK-dependent manner[1].KIN-8194 (0-1 μM, 30 min) inhibits adhesion of MCL cells ( JeKo-1 and Granta-519) to fibronectin or stromal cells in an HCK-dependent manner[1].
KIN-8194 (12.5-50 mg/kg, p.o., once time) blocks pHCK and pBTK in a dose-dependent manner in MYD88-mutated TMD-8 ABC DLBCL xenograft mouse model[2].KIN-8194 (50 mg/kg, p.o., daily, 6 weeks) inhibits tumor growth in MYD88-mutated TMD-8 ABC DLBCL xenograft mouse model[2].KIN-8194 (30 mg/kg, p.o., daily, 22 days) combined with Venetoclax prolongs the survival of ibrutinib-resistant BTKCys481Ser TMD-8 cells xenograft mice median survival time[2].
References:
[1]. Lantermans HC, et al. The dual HCK/BTK inhibitor KIN-8194 impairs growth and integrin-mediated adhesion of BTKi-resistant mantle cell lymphoma. Leukemia. 2024 Mar 7.
[2]. Yang G, et al. The HCK/BTK inhibitor KIN-8194 is active in MYD88-driven lymphomas and overcomes mutated BTKCys481 ibrutinib resistance. Blood. 2021 Nov 18;138(20):1966-1979.