Mechanism of action: Transient inhibitor of cyclin dependent kinase 9 (CDK9)
AZD4573 is a CDK9 inhibitor suitable for IV administration designed for transient target engagement in man. Transient CDK9 inhibition with AZD4573 provides a mechanism to indirectly down modulate key cell survival proteins such as Mcl-1 to kill tumor cells.
In biochemical assays (FRET) AZD4573 is both highly potent against CDK9 (<3nM IC50) and selective (>10 fold) against all other CDKs and kinases.
AZD4573 treatment causes a rapid dose- and time-dependent decrease in pSer2-RNAPII with concomitant loss of Mcl-1 and MYC mRNA and protein, resulting in caspase induction and loss of cell viability. In human cancer cell line panel screens, AZD4573 induces rapid caspase activation (6h) and loss of viability (24h) across a diverse set of hematological cancers (median caspase EC50=30nM, GI50=11nM) but has minimal effect on solid tumors (median EC50 & GI50 >30μM).
In mice xenograft studies AZD4573 causes durable regressions in subcutaneous and disseminated models of MM and AML and NHL. AZD4573 also significantly enhances the antitumor activity of venetoclax in in vitro and in vivo models of AML, MM and NHL, and the activity of acalabrutinib in NHL cell lines and subcutaneous xenografts.
Suitable for and exclusions
Restricted to preclinical oncology studies (proposals) only.