AZD-5991 is a potent and selective Mcl-1 inhibitor [IC50: 0.7 nM in FRET assay; Kd: 0.17 nM in SPR assay].

MCL1:0.17 nM (kd), MCL1:0.7 nM

AZD-5991 is selective for Mcl-1 (IC50: 0.72?nM, Ki: 200?pM) vs. Bcl-2 (IC50: 20?μM, Ki: 6.8?μM), Bcl-xL (IC50: 36?μM, Ki: 18?μM), Bcl-w (IC50: 49?μM, Ki: 25?μM), and Bfl-1 (IC50: 24?μM, Ki: 12?μM). MOLP-8, MV4-11, and NCI-H23 cells are treated with AZD5991 (EC50: 0.033, 0.024, 0.19?μM, respectively). AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 reduces the levels of Mcl-1 protein in AZD5991-sensitive but not in AZD5991-resistant MM cell lines.

Administration of a single intravenous (i.v.) dose of AZD5991 results in a dose-dependant antitumor effect, varying from tumor growth inhibition (TGI) to complete tumor regression (TR). Specifically, 10 days post-treatment, TGI is observed at 52% and 93% for doses of 10 and 30 mg/kg respectively. Remarkably, at a dose of 60 mg/kg, 99% TR is achieved with no detectable tumors in 6 of 7 mice, and at 100 mg/kg, complete TR is observed in all mice treated. Furthermore, AZD5991 demonstrates a dose-dependent duration of response, with tumors at the 100 mg/kg dose regrowing later than those at the 60 mg/kg dose. The efficacy of AZD5991 in vivo directly correlates with the activation of caspase-3 within the tumor and the drug's plasma concentration. The compound is well-tolerated across all dosages without significant weight loss in treated mice. A notable observation is the sustained effect of AZD5991, where a second dose administered 36 days following the initial dose induces tumor regression in all treated mice. Additionally, consecutive dosing at 100 mg/kg on days 0 and 1 results in a longer delay in tumor regrowth compared to a single dose at the same concentration, showcasing the compound's potent and durable antitumor activity.