AZD-5991

AZD-5991 is a potent and selective Mcl-1 inhibitor with an IC50 of 0.7 nM in FRET assay and a Kd of 0.17 nM in surface plasmon resonance (SPR) assay.

Product information

CAS Number: 2143061-81-6

Molecular Weight: 672.26

Formula: C35H34ClN5O3S2

Chemical Name: 17-chloro-5,13,14,22-tetramethyl-28-oxa-2,9-dithia-5,6,12,13,22-pentaazaheptacyclo[27.7.1.1⁴,⁷.0¹¹,¹⁵.0¹⁶,²¹.0²⁰,²⁴.0³⁰,³⁵]octatriaconta-1(37),4(38),6,11,14,16,18,20,23,29,31,33,35-tridecaene-23-carboxylic acid

Smiles: CC1=C2C3=C(Cl)C=CC4=C3N(C)C(C(O)=O)=C4CCCOC3C=C(C=C4C=CC=CC4=3)SCC3=CC(CSCC2=NN1C)=NN3C

InChiKey: KBQCEQAXHPIRTF-UHFFFAOYSA-N

InChi: InChI=1S/C35H34ClN5O3S2/c1-20-31-29(38-40(20)3)19-45-17-22-15-23(41(4)37-22)18-46-24-14-21-8-5-6-9-25(21)30(16-24)44-13-7-10-26-27-11-12-28(36)32(31)33(27)39(2)34(26)35(42)43/h5-6,8-9,11-12,14-16H,7,10,13,17-19H2,1-4H3,(H,42,43)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO : 25 mg/mL (37.19 mM; Need ultrasonic).

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

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.

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.

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