6B3E

Crystal structure of human CDK12/CyclinK in complex with an inhibitor

Summary for 6B3E

• Entry DOI: 10.2210/pdb6b3e/pdb
• Descriptor: Cyclin-dependent kinase 12, Cyclin-K, MAGNESIUM ION, ... (6 entities in total)
• Functional Keywords: inhibitor, complex, kinase, transferase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus: Q9NYV4 O75909
• Total number of polymer chains: 4
• Total formula weight: 138147.99

Authors

Ferguson, A.D. (deposition date: 2017-09-21, release date: 2017-12-27, Last modification date: 2024-11-13)

Primary citation

Johannes, J.W.,Denz, C.R.,Su, N.,Wu, A.,Impastato, A.C.,Mlynarski, S.,Varnes, J.G.,Prince, D.B.,Cidado, J.,Gao, N.,Haddrick, M.,Jones, N.H.,Li, S.,Li, X.,Liu, Y.,Nguyen, T.B.,O'Connell, N.,Rivers, E.,Robbins, D.W.,Tomlinson, R.,Yao, T.,Zhu, X.,Ferguson, A.D.,Lamb, M.L.,Manchester, J.I.,Guichard, S.
Structure-Based Design of Selective Noncovalent CDK12 Inhibitors.
ChemMedChem, 13:231-235, 2018

PubMed Abstract: Cyclin-dependent kinase (CDK) 12 knockdown via siRNA decreases the transcription of DNA-damage-response genes and sensitizes BRCA wild-type cells to poly(ADP-ribose) polymerase (PARP) inhibition. To recapitulate this effect with a small molecule, we sought a potent, selective CDK12 inhibitor. Crystal structures and modeling informed hybridization between dinaciclib and SR-3029, resulting in lead compound 5 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-ethyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Further structure-guided optimization delivered a series of selective CDK12 inhibitors, including compound 7 [(S)-2-(1-(6-(((6,7-difluoro-1H-benzo[d]imidazol-2-yl)methyl)amino)-9-isopropyl-9H-purin-2-yl)piperidin-2-yl)ethan-1-ol]. Profiling of this compound across CDK9, 7, 2, and 1 at high ATP concentration, single-point kinase panel screening against 352 targets at 0.1 μm, and proteomics via kinase affinity matrix technology demonstrated the selectivity. This series of compounds inhibits phosphorylation of Ser2 on the C-terminal repeat domain of RNA polymerase II, consistent with CDK12 inhibition. These selective compounds were also acutely toxic to OV90 as well as THP1 cells.

PubMed: 29266803
DOI: 10.1002/cmdc.201700695

Experimental method

X-RAY DIFFRACTION (3.06 Å)