PDBsum entry 6b3e

Transferase/inhibitor

PDB id: 6b3e

Contents

Protein chains

310 a.a.

240 a.a.

Ligands

CJM ×2

EDO ×3

Metals

_MG ×2

Waters ×9

PDB id:

6b3e

Name:

Transferase/inhibitor

Title:

Crystal structure of human cdk12/cyclink in complex with an inhibitor

Structure:

Cyclin-dependent kinase 12. Chain: a, c. Synonym: cdc2-related kinase,arginine/serine-rich,crkrs,cell division cycle 2-related protein kinase 7,cdc2-related protein kinase 7,cell division protein kinase 12,hcdk12. Engineered: yes. Cyclin-k. Chain: b, d. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk12, crk7, crkrs, kiaa0904. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: ccnk, cpr4. Expression_system_taxid: 7108

Resolution:

3.06Å R-factor: 0.191 R-free: 0.212

Authors:

A.D.Ferguson

Key ref:

J.W.Johannes et al. (2018). Structure-Based Design of Selective Noncovalent CDK12 Inhibitors. ChemMedChem, 13, 231-235. PubMed id: 29266803 DOI: 10.1002/cmdc.201700695

Date:

21-Sep-17 Release date: 27-Dec-17

Protein chains

Q9NYV4  (CDK12_HUMAN) -  Cyclin-dependent kinase 12 from Homo sapiens

Seq: 1490 a.a.

Struc: 310 a.a.*

Protein chains

O75909  (CCNK_HUMAN) -  Cyclin-K from Homo sapiens

Seq: 580 a.a.

Struc: 240 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 2: Chains A, C: E.C.2.7.11.22 - cyclin-dependent kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺
• Enzyme class 3: Chains A, C: E.C.2.7.11.23 - [RNA-polymerase]-subunit kinase.
• Reaction: [DNA-directed RNA polymerase] + ATP = phospho-[DNA-directed RNA polymerase] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1002/cmdc.201700695

ChemMedChem 13:231-235 (2018)

PubMed id: 29266803

Structure-Based Design of Selective Noncovalent CDK12 Inhibitors.

J.W.Johannes, C.R.Denz, N.Su, A.Wu, A.C.Impastato, S.Mlynarski, J.G.Varnes, D.B.Prince, J.Cidado, N.Gao, M.Haddrick, N.H.Jones, S.Li, X.Li, Y.Liu, T.B.Nguyen, N.O'Connell, E.Rivers, D.W.Robbins, R.Tomlinson, T.Yao, X.Zhu, A.D.Ferguson, M.L.Lamb, J.I.Manchester, S.Guichard.

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.