AZD 5991

Research use only, not for human use.

AZD 5991 (AZD5991) is a potent and selective macrocyclic inhibitor of Mcl-1 with sub-nanomolar affinity.

AZD 5991 (AZD5991) is a potent and selective macrocyclic inhibitor of Mcl-1 with sub-nanomolar affinity; promotes rapid apoptosis in Mcl-1-dependent cell lines (GI50=10 nM in multiple myeloma cell lines), disrupts Mcl-1/Bak complex; completely causes tumor regression in several mouse xenograft models after a single tolerated dose.Blood Cancer Phase 1 Clinical(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, 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, 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.

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, 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, 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.

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.

AZD5991

Angiogenesis

Bcl-2

Bcl-2

Cancer

Blood cancer

2143061-81-6

672.259

C35H34ClN5O3S2

>98% (HPLC)

DMSO : 41.67 mg/mL 61.98 mM; H2O : < 0.1 mg/mL

CC1=C2C(=NN1C)CSCC3=NN(C(=C3)CSC4=CC5=CC=CC=C5C(=C4)OCCCC6=C(N(C7=C6C=CC(=C27)Cl)C)C(=O)O)C

(Z)-16-chloro-11,21,25,61-tetramethyl-11H,21H,61H-10-oxa-4,8-dithia-1(7,3)-indola-2(4,3),6(3,5)-dipyrazola-9(3,1)-naphthalenacyclotridecaphane-12-carboxylic acid

(-20℃)

With Ice Pack

≥ 2 years