6Z45

CDK9-Cyclin-T1 complex bound by compound 24

Summary for 6Z45

• Entry DOI: 10.2210/pdb6z45/pdb
• Descriptor: Cyclin-dependent kinase 9, Cyclin-T1, (1~{S},3~{R})-3-acetamido-~{N}-[5-chloranyl-4-(5,5-dimethyl-4,6-dihydropyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl]cyclohexane-1-carboxamide, ... (5 entities in total)
• Functional Keywords: inhibitor, complex, kinase, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 68597.23

Authors

Ferguson, A.,Collie, G.W. (deposition date: 2020-05-22, release date: 2020-12-23, Last modification date: 2024-11-20)

Primary citation

Barlaam, B.,Casella, R.,Cidado, J.,Cook, C.,De Savi, C.,Dishington, A.,Donald, C.S.,Drew, L.,Ferguson, A.D.,Ferguson, D.,Glossop, S.,Grebe, T.,Gu, C.,Hande, S.,Hawkins, J.,Hird, A.W.,Holmes, J.,Horstick, J.,Jiang, Y.,Lamb, M.L.,McGuire, T.M.,Moore, J.E.,O'Connell, N.,Pike, A.,Pike, K.G.,Proia, T.,Roberts, B.,San Martin, M.,Sarkar, U.,Shao, W.,Stead, D.,Sumner, N.,Thakur, K.,Vasbinder, M.M.,Varnes, J.G.,Wang, J.,Wang, L.,Wu, D.,Wu, L.,Yang, B.,Yao, T.
Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies.
J.Med.Chem., 63:15564-15590, 2020

PubMed Abstract: 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 ), focusing on properties suitable for achieving short target engagement after intravenous administration. By increasing potency and human metabolic clearance, we identified compound , a potent and selective CDK9 inhibitor with suitable predicted human pharmacokinetic properties to deliver transient inhibition of CDK9. Furthermore, the solubility of was considered adequate to allow i.v. formulation at the anticipated effective dose. Short-term treatment with compound 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 demonstrated efficacy in xenograft models derived from multiple hematological tumors. Compound is currently in clinical trials for the treatment of hematological malignancies.

PubMed: 33306391
DOI: 10.1021/acs.jmedchem.0c01754

Experimental method

X-RAY DIFFRACTION (3.37 Å)