AZD5991
Preclinical pharmacology
AZD5991 is a direct inhibitor of Mcl-1 with <1nM 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= 33nM; MV4;11 EC50=24nM). AZD5991 has a binding affinity >10,000-fold lower 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 <100nM. In solid tumor cell lines single agent activity was seen mostly in NSCLC and BrCa.
AZD5991 showed ex vivo activity in primary cells from patients with MM [24h Annexin V EC50 <100nM seen in 34/48 (71%) of samples].
In mice xenograft studies AZD5991 caused tumor regressions after a single iv dose in subcutaneous and disseminated models of MM and AML. Induction of cleaved caspase 3 was detected as soon as 30 min after iv bolus injection. AZD5991 also 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
Currently available for preclinical oncology studies only.
Mechanism of Action
BH3 mimetic inhibitor of the anti-apoptotic protein Mcl-1
Original Therapeutic Area
Oncology
CNS Penetrant
Unknown
Route of administration
IV
Modality
Small Molecule
Additional Information
1. Tron AE., et al. (2018).
Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia. Nat Commun 9, 5341. DOI: 10.1038/s41467-018-07551-w.