In Vitro: BTK inhibition is an effective approach against B-cell malignancies. BTK-IN-15 (compound 42) demonstrates inhibitory against TMD8 with an IC50 value of 2.6 nM. BTK-IN-15 (1 μM; 1 h) displays significant selectivity to BTK over EGFR kinase with 0.05% and 44% of the control, respectively. BTK-IN-15 (0-1 mM; 72 h) exerts potent anti-proliferative activity against a human mantle cell lymphoma cell line (REC-1) with an IC50 value of 1.7 nM. BTK-IN-15 (0-1 mM; 2 h) inhibits BTK auto-phosphorylation with an IC50 value of 1.49 nM. BTK-IN-15 (0-100 nM; 48 h) arrests cell cycle at G1 phase and (0-1 mM; 72 h) induces apoptosis in TMD8. BTK-IN-15 shows low hERG channel activity (IC50=4.38 μM), indicating low cardiotoxicity.
In Vivo: BTK-IN-15 (compound 42) (12.5-50 mg/kg; p.o.; twice daily; 21 d) inhibits tumor growth (TGI = 104%) at a dosage of 50 mg/kg in mice. BTK-IN-15 (300, 400, 500 mg/kg; p.o.; twice daily; 14 d) has biological safety and displays no affect against body weight in mice compared with control. BTK-IN-15 (10 mg/kg; p.o.) shows a high oral bioavailability of 40.98% in mice. Pharmacokinetics of BTK-IN-15 in Mice