AZD4573 is a potent inhibitor of CDK9 (IC50 of <0.004 μM) with fast-off binding kinetics (t1/2 = 16 min) and high selectivity versus other kinases, including other CDK family kinases.
Short-term treatment with AZD4573 leads to a rapid dose- and time-dependent decrease in cellular pSer2-RNAPII, resulting in activation of caspase 3 and cell apoptosis in a broad range of haematological cancer cell lines (e.g. caspase activation EC50 0.0137 μM in an acute myeloid leukemia model MV4-11)[1]. In human cancer cell line panel screens, AZD4573 demonstrates the ability to induce rapid caspase activation (6h) and loss of viability (24h) across a diverse set of hematological cancers (median caspase EC50 = 30 nM, GI50 = 11 nM) but with minimal effect on solid tumors (median EC50 & GI50 >30 μM)[2].
AZD4573 exhibits a short half-life in multiple preclinical species (less than one hour in rat, dog and monkey) and good solubility for intravenous administration[1].
[1] Bernard Barlaam, et al. AACR Cancer Res. 2018, 78(13 Suppl):Abstract nr 1650. [2] Justin Cidado, et al. AACR Cancer Res. 2018, 78(13 Suppl):Abstract nr 310.