KIN-8194 is a dual inhibitor of HCK and BTK, effective when administered orally, displaying IC 50 values of 0.915 nM for HCK and <0.495 nM for BTK. It inhibits growth and disrupts integrin-mediated adhesion in BTKi-resistant mantle cell lymphoma (MCL). Additionally, KIN-8194 has shown efficacy in overcoming ibrutinib resistance, enhancing survival in TMD-8 ABC DLBCL xenografted mice [1] [2].

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]. It reduces proliferation in MCL cell lines by inhibiting HCK [1]. At 100 nM for 6 hours, KIN-8194 suppresses the AKT-S6 signaling pathway in Maver-1 and Granta-519 cells in an HCK-dependent manner [1]. Additionally, KIN-8194 (0-1 μM, 30 minutes) inhibits adhesion of MCL cells (JeKo-1 and Granta-519) to fibronectin or stromal cells in an HCK-dependent fashion [1].

KIN-8194, administered orally at doses ranging from 12.5 to 50 mg/kg, dose-dependently inhibits pHCK and pBTK in MYD88-mutated TMD-8 ABC DLBCL xenograft mouse models. Additionally, a daily oral dose of 50 mg/kg over six weeks suppresses tumor growth in these models. Furthermore, a 30 mg/kg daily oral dose of KIN-8194 combined with Venetoclax extends median survival in ibrutinib-resistant BTK Cys481Ser TMD-8 cell xenograft mice [2].