Mcl-1 inhibitor 3 shows good pharmacokinetic properties and excellent in vivo efficacy without toxicity.Mcl-1 inhibitor 3 is a highly potent and orally activate macrocyclic Mcl-1 inhibitor (Ki= 0.061 nM; IC50=19 nM in an OPM-2 cell viability assay).

MCL1:0.061 nM (ki), MCL1:19 nM

Mcl-1 inhibitor 3 exhibits an IC50 of 19 nM in an OPM-2 cell viability assay and a Ki of 0.061 nM in an Mcl-1 HTRF/TR-FRET assay.

Mcl-1 inhibitor 3 (oral administration; 10, 30, or 60 mg/kg; 30 days) led to robust dose-dependent tumor growth inhibition at 30 mg/kg (44% TGI) and 34% tumor regression at 60 mg/kg without any body weight loss in the mice. Mcl-1 inhibitor 3 (oral administration; 3, 10, or 30 mg/kg; 6 hours) resulted in significant luminescence loss (~40%) at 30 mg/kg, with corresponding unbound drug levels in plasma showing [plasma]u/OPM-2 IC50 values of 0.24, 0.93, and 3.65 μM at 3, 10, and 30 mg/kg, respectively. Additionally, Mcl-1 inhibitor 3 (oral administration; 10, 30, or 60 mg/kg; 6 hours) activated Bak by 8-fold at 30 mg/kg and by 14-fold at 60 mg/kg in the OPM-2 Luc assay, based on the detection of activated Bak in nude mice via electrochemiluminescence.