Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies

A CDK9
inhibitor having short target engagement would enable a
reduction of Mcl-1 activity, resulting in apoptosis in cancer cells
dependent on Mcl-1 for survival. We report the optimization of a series
of amidopyridines (from compound 2), focusing on properties
suitable for achieving short target engagement after intravenous administration.
By increasing potency and human metabolic clearance, we identified
compound 24, a potent and selective CDK9 inhibitor with
suitable predicted human pharmacokinetic properties to deliver transient
inhibition of CDK9. Furthermore, the solubility of 24 was considered adequate to allow i.v. formulation at the anticipated
effective dose. Short-term treatment with compound 24 led to a rapid dose- and time-dependent decrease of pSer2-RNAP2
and Mcl-1, resulting in cell apoptosis in multiple hematological cancer
cell lines. Intermittent dosing of compound 24 demonstrated
efficacy in xenograft models derived from multiple hematological tumors.
Compound 24 is currently in clinical trials for the treatment
of hematological malignancies.