2. Academic Validation
  3. Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines

Cyclin-Dependent Kinase (CDK) Inhibitors: Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines

  • J Med Chem. 2017 Mar 9;60(5):1746-1767. doi: 10.1021/acs.jmedchem.6b01254.
Christopher R Coxon 1,  Elizabeth Anscombe 2,  Suzannah J Harnor 1,  Mathew P Martin 3,  Benoit Carbain 1,  Bernard T Golding 1,  Ian R Hardcastle 1,  Lisa K Harlow 1,  Svitlana Korolchuk 3,  Christopher J Matheson 1,  David R Newell 3,  Martin E M Noble 2,  Mangaleswaran Sivaprakasam 1,  Susan J Tudhope 3,  David M Turner 1,  Lan Z Wang 3,  Stephen R Wedge 3,  Christopher Wong 1,  Roger J Griffin 1,  Jane A Endicott 2,  Céline Cano 1
Affiliations

Affiliations

  • 1 Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University , Bedson Building, Newcastle upon Tyne NE1 7RU, U.K.
  • 2 Department of Biochemistry, University of Oxford , South Parks Road, Oxford, OX1 3QU, U.K.
  • 3 Newcastle Cancer Centre, Northern Institute for Cancer Research, Newcastle University Medical School , Paul O'Gorman Building, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K.
PMID: 28005359 DOI: 10.1021/acs.jmedchem.6b01254
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 (IC50 0.044 μM) but was ∼2000-fold less active toward CDK1 (IC50 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-117535
    98.07%, CDK2抑制剂
    CDK
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z