AZD-5991

AZD-5991 is a potent and selective Mcl-1 inhibitor with an IC₅₀ of 0.7 nM in FRET assay and a K_d of 0.17 nM in surface plasmon resonance (SPR) assay^[1]. In Vitro: The selectivity of AZD-5991 is evaluated against pro-survival Bcl-2 family members using FRET assays. AZD-5991 is selective for Mcl-1 (IC₅₀ 0.72 nM, K_i=200 pM) vs. Bcl-2 (IC₅₀=20 µM, K_i=6.8 µM), Bcl-xL (IC₅₀=36 µM, K_i=18 µM), Bcl-w (IC₅₀=49 µM, K_i=25 µM), and Bfl-1 (IC₅₀=24 µM, K_i=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, most notably myeloma and acute myeloid leukemia, 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 further supporting the notion that activation of caspases by AZD5991 reduces Mcl-1 protein levels in AZD5991-sensitive cell lines^[1]. In Vivo: A single intravenous (i.v.) dose of AZD5991 leads to a dose-dependent antitumor effect ranging from tumor growth inhibition (TGI) to tumor regression (TR). Ten days after treatment, AZD5991 shows 52% and 93% TGI (p<0.0001) at 10 and 30 mg/kg, respectively. At the same time point, AZD5991 at 60 mg/kg leads to 99% TR with no detectable tumors in 6 out of 7 mice, while complete TR is seen in 7 out of 7 mice in the 100 mg/kg dose group. AZD5991 also shows a dose-dependent duration of response with tumors in the 100 mg/kg group growing back later than those in the 60 mg/kg group. The magnitude of in vivo tumor efficacy is correlated with activation of caspase-3 in the tumor and concentration of AZD5991 in plasma. Treatment with AZD5991 was well tolerated at all dose levels with no significant body weight loss. A single dose of AZD5991 36 days after the first dose causes tumor regression in 4 out of 4 mice. In mice dosed with AZD5991 at 100 mg/kg on day 0 and day 1, tumors grow back later than those dosed with a single dose of AZD5991 at the same dose level^[1].