PDBsum entry 3s00

Transferase/transferase inhibitor

PDB id: 3s00

Contents

Protein chain

294 a.a.

Ligands

Z60

Waters ×162

PDB id:

3s00

Name:

Transferase/transferase inhibitor

Title:

Cdk2 in complex with inhibitor l4-14

Structure:

Cyclin-dependent kinase 2. Chain: a. Synonym: cdk2, cell division protein kinase 2, p33 protein kinase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: cdk2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.80Å R-factor: 0.216 R-free: 0.251

Authors:

S.Betzi,R.Alam,H.Han,A.Becker,E.Schonbrunn

Key ref:

E.Schonbrunn et al. (2013). Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases. J Med Chem, 56, 3768-3782. PubMed id: 23600925 DOI: 10.1021/jm301234k

Date:

12-May-11 Release date: 31-Oct-12

Protein chain

P24941  (CDK2_HUMAN) -  Cyclin-dependent kinase 2 from Homo sapiens

Seq: 298 a.a.

Struc: 294 a.a.

Enzyme reactions

• Enzyme class: 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⁺

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

reference

DOI no: 10.1021/jm301234k

J Med Chem 56:3768-3782 (2013)

PubMed id: 23600925

Development of highly potent and selective diaminothiazole inhibitors of cyclin-dependent kinases.

E.Schonbrunn, S.Betzi, R.Alam, M.P.Martin, A.Becker, H.Han, R.Francis, R.Chakrasali, S.Jakkaraj, A.Kazi, S.M.Sebti, C.L.Cubitt, A.W.Gebhard, L.A.Hazlehurst, J.S.Tash, G.I.Georg.

ABSTRACT

Cyclin-dependent kinases (CDKs) are serine/threonine protein kinases that act as key regulatory elements in cell cycle progression. We describe the development of highly potent diaminothiazole inhibitors of CDK2 (IC50 = 0.0009-0.0015 μM) from a single hit compound with weak inhibitory activity (IC50 = 15 μM), discovered by high-throughput screening. Structure-based design was performed using 35 cocrystal structures of CDK2 liganded with distinct analogues of the parent compound. The profiling of compound 51 against a panel of 339 kinases revealed high selectivity for CDKs, with preference for CDK2 and CDK5 over CDK9, CDK1, CDK4, and CDK6. Compound 51 inhibited the proliferation of 13 out of 15 cancer cell lines with IC50 values between 0.27 and 6.9 μM, which correlated with the complete suppression of retinoblastoma phosphorylation and the onset of apoptosis. Combined, the results demonstrate the potential of this new inhibitors series for further development into CDK-specific chemical probes or therapeutics.