6GVA

CDK2/cyclin A2 in complex with pyrazolo[4,3-d]pyrimidine inhibitor LGR4455

Summary for 6GVA

• Entry DOI: 10.2210/pdb6gva/pdb
• Descriptor: Cyclin-dependent kinase 2, Cyclin-A2, 5-(2-azanylethylsulfanyl)-3-propan-2-yl-~{N}-[(4-pyridin-2-ylphenyl)methyl]-2~{H}-pyrazolo[4,3-d]pyrimidin-7-amine, ... (10 entities in total)
• Functional Keywords: cyclin-dependent kinase, pyrazolo[4, 3-d]pyrimidine, cell cycle
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 64941.51

Authors

Skerlova, J.,Rezacova, P. (deposition date: 2018-06-20, release date: 2019-05-01, Last modification date: 2024-10-23)

Primary citation

Jorda, R.,Havlicek, L.,Sturc, A.,Tuskova, D.,Daumova, L.,Alam, M.,Skerlova, J.,Nekardova, M.,Perina, M.,Pospisil, T.,Siroka, J.,Urbanek, L.,Pachl, P.,Rezacova, P.,Strnad, M.,Klener, P.,Krystof, V.
3,5,7-Substituted Pyrazolo[4,3- d]pyrimidine Inhibitors of Cyclin-Dependent Kinases and Their Evaluation in Lymphoma Models.
J.Med.Chem., 62:4606-4623, 2019

PubMed Abstract: Cyclin-dependent kinases are therapeutic targets frequently deregulated in various cancers. By convenient alkylation of the 5-sulfanyl group, we synthesized 3-isopropyl-7-[4-(2-pyridyl)benzyl]amino-1(2) H-pyrazolo[4,3- d]pyrimidines with various substitutions at position 5 with potent antiproliferative activity in non-Hodgkin lymphoma cell lines. The most potent derivative 4.35 also displayed activities across more than 60 cancer cell lines. The kinase profiling confirmed high selectivity of 4.35 toward cyclin-dependent kinases (CDKs) 2, 5, and 9, and the cocrystal with CDK2/cyclin A2 revealed its binding in the active site. Cultured lymphoma cell lines treated with 4.35 showed dephosphorylation of CDK substrates, cleavage of PARP-1, downregulation of XIAP and MCL-1, and activation of caspases, which collectively confirmed ongoing apoptosis. Moreover, 4.35 demonstrated significant activity in various cell line xenograft and patient-derived xenograft mouse models in vivo both as a monotherapy and as a combination therapy with the BCL2-targeting venetoclax. These findings support further studies of combinatorial treatment based on CDK inhibitors.

PubMed: 30943029
DOI: 10.1021/acs.jmedchem.9b00189

Experimental method

X-RAY DIFFRACTION (2.15 Å)