Barlaam, Bernard published the artcileDiscovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies, Application In Synthesis of 2057507-56-7, the publication is Journal of Medicinal Chemistry (2020), 63(24), 15564-15590, database is CAplus and MEDLINE.
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 i.v. 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 ED. 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 hematol. cancer cell lines. Intermittent dosing of compound 24 demonstrated efficacy in xenograft models derived from multiple hematol. tumors. Compound 24 is currently in clin. trials for the treatment of hematol. malignancies.
Journal of Medicinal Chemistry published new progress about 2057507-56-7. 2057507-56-7 belongs to pyrazoles-derivatives, auxiliary class Pyrazoles, name is 3-Bromo-5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole, and the molecular formula is C8H11BrN2, Application In Synthesis of 2057507-56-7.
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