2. Academic Validation
  3. Discovery of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors

Discovery of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amine aurora kinase inhibitors

  • J Med Chem. 2010 Jun 10;53(11):4367-78. doi: 10.1021/jm901913s.
Shudong Wang 1,  Carol A Midgley,  Frederic Scaërou,  Joanna B Grabarek,  Gary Griffiths,  Wayne Jackson,  George Kontopidis,  Steven J McClue,  Campbell McInnes,  Christopher Meades,  Mokdad Mezna,  Andy Plater,  Iain Stuart,  Mark P Thomas,  Gavin Wood,  Rosemary G Clarke,  David G Blake,  Daniella I Zheleva,  David P Lane,  Robert C Jackson,  David M Glover,  Peter M Fischer
Affiliations

Affiliation

  • 1 Cyclacel Ltd., 1 James Lindsay Place, Dundee DD1 5JJ, Scotland, UK.
PMID: 20462263 DOI: 10.1021/jm901913s
Abstract

Through cell-based screening of our kinase-directed compound collection, we discovered that a subset of N-phenyl-4-(thiazol-5-yl)pyrimidin-2-amines were potent cytotoxic agents against Cancer cell lines, suppressed mitotic histone H3 phosphorylation, and caused aberrant mitotic phenotypes. It was subsequently established that these compounds were in fact potent inhibitors of Aurora A and B kinases. It was shown that potency and selectivity of Aurora Kinase inhibition correlated with the presence of a substituent at the aniline para-position in these compounds. The Anticancer effects of lead compound 4-methyl-5-(2-(4-morpholinophenylamino)pyrimidin-4-yl)thiazol-2-amine (18; K(i) values of 8.0 and 9.2 nM for Aurora A and B, respectively) were shown to emanate from cell death following mitotic failure and increased polyploidy as a consequence of cellular inhibition of Aurora A and B kinases. Preliminary in vivo assessment showed that compound 18 was orally bioavailable and possessed Anticancer activity. Compound 18 (CYC116) is currently undergoing phase I clinical evaluation in Cancer patients.

Figures
Products
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