Targeting CDK9 with AZD4573: A Promising Therapeutic Approach for Hematologic Cancers

Cyclin-dependent kinase 9 (CDK9) is a key enzyme that controls the elongation phase of transcription by phosphorylating RNA polymerase II. Inhibiting CDK9 offers a therapeutic strategy for cancers reliant on short-lived transcripts and proteins, such as those dependent on the anti-apoptotic protein Mcl-1. A CDK9 inhibitor with a rapid onset and short duration of action could be advantageous in the clinical setting, providing a flexible approach to treatment.

The development of AZD4573 is highlighted, which is an optimized CDK9 inhibitor with improved pharmacokinetic and physicochemical properties suitable for intravenous administration and short-term target engagement. The process involved enhancing metabolic clearance for a brief half-life and solubility while maintaining potency. AZD4573 is characterized by its high potency (IC50 < 0.004 μM), fast dissociation from the target (t1/2 of 16 minutes), and selectivity over other kinases, including the CDK family.

In preclinical studies, AZD4573 demonstrated a short half-life across different species and was effective in inducing rapid decreases in cellular pSer2-RNAPII levels, leading to caspase activation and apoptosis in various hematological cancer cell lines. For instance, in an acute myeloid leukemia model (MV4-11), caspase activation was achieved with an EC50 of 0.0137 μM. AZD4573 also showed in vivo efficacy in xenograft models of hematological tumors, with tumor regression observed at a dosage of 15 mg/kg administered twice weekly.

The findings suggest that AZD4573 is a promising candidate for clinical development for the treatment of hematologic malignancies, with the first disclosure of its structure presented at the meeting.

This research was presented by Bernard Barlaam, Chris De Savi, and colleagues at the American Association for Cancer Research Annual Meeting in 2018.