Mechanism of action: BH3 mimetic inhibitor of the anti-apoptotic protein Mcl-1

Preclinical pharmacology

AZD5991 is a direct inhibitor of Mcl-1 with <1 nM potency in biochemical assays (FRET) and is able to induce intrinsic apoptosis in cells with 6h caspase EC50 values in the low nM range (MOLP8 EC50= 33 nM; MV4;11 EC50=24 nM).  AZD5991 is exquisitely selective for Mcl-1 with >10,000-fold lower affinity for other members of the Bcl-2 family.

Binding affinity of AZD5991 is 25-fold lower for mouse Mcl-1, 4-fold lower for rat Mcl-1 and similar for dog Mcl-1 compared to human Mcl-1.

AZD5991 monotherapy caused apoptosis preferentially in hematological cell lines with 6/22 AML and 7/19 MM cell lines showing caspase EC50 values <100 nM.  In solid tumor cell lines single agent activity was seen mostly in NSCLC and BrCa (see publication mentioned below).

AZD5991 showed ex vivo activity in primary cells from patients with MM [24h Annexin V EC50 <100 nM seen in 34/48 (71%) of samples].

In mice xenograft studies AZD5991 caused tumor regressions after a single i.v. dose in subcutaneous and disseminated models of MM and AML.  Induction of cleaved caspase 3 was detected as soon as 30 min after i.v. bolus injection.  AZD5991 also significantly enhanced the antitumor activity of venetoclax in in vitro and in vivo models of AML, MM and NHL, and the activity of bortezomib in MM cell lines and subcutaneous xenografts.

Suitable for and exclusions

Restricted to preclinical oncology studies (proposals) only.

Additional Information

Clinical Trials for this compound

See all of the Clinical Trials currently associated with this compound:

Publications for this compound

Tron, A. E. et al.  Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia, Nat Commun. 9 (2018)

Gene information from the NCBi

This compound works on the following genes: