5CYI

CDK2/Cyclin A covalent complex with 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300)

Summary for 5CYI

• Entry DOI: 10.2210/pdb5cyi/pdb
• Descriptor: Cyclin-dependent kinase 2, Cyclin-A2, 6-(cyclohexylmethoxy)-N-[4-(ethylsulfonyl)phenyl]-9H-purin-2-amine, ... (4 entities in total)
• Functional Keywords: cdk2 cyclin a covalent inhibitor vinylsulphone, transferase
• Biological source: Homo sapiens (Human); More
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941; Nucleus : P20248
• Total number of polymer chains: 4
• Total formula weight: 129536.08

Authors

Anscombe, E.,Meschini, E.,Vidal, R.M.,Martin, M.P.,Staunton, D.,Geitmann, M.,Danielson, U.H.,Stanley, W.A.,Wang, L.Z.,Reuillon, T.,Golding, B.T.,Cano, C.,Newell, D.R.,Noble, M.E.M.,Wedge, S.R.,Endicott, J.A.,Griffin, R.J. (deposition date: 2015-07-30, release date: 2015-09-16, Last modification date: 2024-11-13)

Primary citation

Anscombe, E.,Meschini, E.,Mora-Vidal, R.,Martin, M.P.,Staunton, D.,Geitmann, M.,Danielson, U.H.,Stanley, W.A.,Wang, L.Z.,Reuillon, T.,Golding, B.T.,Cano, C.,Newell, D.R.,Noble, M.E.,Wedge, S.R.,Endicott, J.A.,Griffin, R.J.
Identification and Characterization of an Irreversible Inhibitor of CDK2.
Chem.Biol., 22:1159-1164, 2015

PubMed Abstract: Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)-9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.

PubMed: 26320860
DOI: 10.1016/j.chembiol.2015.07.018

Experimental method

X-RAY DIFFRACTION (2 Å)