8b54

CDK2/cyclin A2 in complex with pyrazolo[4,3-d]pyrimidine inhibitor LGR6768

spinqualitylabelsall models 8b54, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8b54 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.6Å Ligands: EDO, GOL, P2V, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Targeting cyclin-dependent kinase 7 (CDK7) provides an interesting therapeutic option in cancer therapy because this kinase participates in regulating the cell cycle and transcription. Here, we describe a new trisubstituted pyrazolo[4,3-d]pyrimidine derivative, LGR6768, that inhibits CDK7 in the nanomolar range and displays favourable selectivity across the CDK family. We determined the structure of fully active CDK2/cyclin A2 in complex with LGR6768 at 2.6 A resolution using X-ray crystallography, revealing conserved interactions within the active site. Structural analysis and comparison with LGR6768 docked to CDK7 provides an explanation of the observed biochemical selectivity, which is linked to a conformational difference in the biphenyl moiety. In cellular experiments, LGR6768 affected regulation of the cell cycle and transcription by inhibiting the phosphorylation of cell cycle CDKs and the carboxy-terminal domain of RNA polymerase II, respectively. LGR6768 limited the proliferation of several leukaemia cell lines, triggered significant changes in protein and mRNA levels related to CDK7 inhibition and induced apoptosis in dose- and time-dependent experiments. Our work supports previous findings and provides further information for the development of selective CDK7 inhibitors. Characterization of new highly selective pyrazolo[4,3-d]pyrimidine inhibitor of CDK7.,Kovalova M, Havlicek L, Djukic S, Skerlova J, Perina M, Pospisil T, Reznickova E, Rezacova P, Jorda R, Krystof V Biomed Pharmacother. 2023 May;161:114492. doi: 10.1016/j.biopha.2023.114492. Epub , 2023 Mar 15. PMID:36931035 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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