5LQF

CDK1/CyclinB1/CKS2 in complex with NU6102

Summary for 5LQF

• Entry DOI: 10.2210/pdb5lqf/pdb
• Descriptor: Cyclin-dependent kinase 1, G2/mitotic-specific cyclin-B1, Cyclin-dependent kinases regulatory subunit 2, ... (5 entities in total)
• Functional Keywords: cdk1 cyclin b cks2 cell cycle nu6102, transferase
• Biological source: Homo sapiens (Human); More
• Cellular location: Nucleus: P06493; Cytoplasm: P14635
• Total number of polymer chains: 6
• Total formula weight: 153233.71

Authors

Coxon, C.R.,Anscombe, E.,Harnor, S.J.,Martin, M.P.,Carbain, B.J.,Hardcastle, I.R.,Harlow, L.K.,Korolchuk, S.,Matheson, C.J.,Noble, M.E.,Newell, D.R.,Turner, D.M.,Sivaprakasam, M.,Wang, L.Z.,Wong, C.,Golding, B.T.,Griffin, R.J.,Endicott, J.A.,Cano, C. (deposition date: 2016-08-17, release date: 2017-01-11, Last modification date: 2024-01-10)

Primary citation

Coxon, C.R.,Anscombe, E.,Harnor, S.J.,Martin, M.P.,Carbain, B.,Golding, B.T.,Hardcastle, I.R.,Harlow, L.K.,Korolchuk, S.,Matheson, C.J.,Newell, D.R.,Noble, M.E.,Sivaprakasam, M.,Tudhope, S.J.,Turner, D.M.,Wang, L.Z.,Wedge, S.R.,Wong, C.,Griffin, R.J.,Endicott, J.A.,Cano, C.
Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines.
J. Med. Chem., 60:1746-1767, 2017

PubMed Abstract: Purines and related heterocycles substituted at C-2 with 4'-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favor competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1'-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency toward CDK2 (IC 0.044 μM) but was ∼2000-fold less active toward CDK1 (IC 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket and that is preferred in CDK2 but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.

PubMed: 28005359
DOI: 10.1021/acs.jmedchem.6b01254

Experimental method

X-RAY DIFFRACTION (2.06 Å)