2. Academic Validation
  3. ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism

ATP-competitive inhibitors of the mitotic kinesin KSP that function via an allosteric mechanism

  • Nat Chem Biol. 2007 Nov;3(11):722-6. doi: 10.1038/nchembio.2007.34.
Lusong Luo 1,  Cynthia A Parrish,  Neysa Nevins,  Dean E McNulty,  Amita M Chaudhari,  Jeffery D Carson,  Valery Sudakin,  Antony N Shaw,  Ruth Lehr,  Huizhen Zhao,  Sharon Sweitzer,  Latesh Lad,  Kenneth W Wood,  Roman Sakowicz,  Roland S Annan,  Pearl S Huang,  Jeffrey R Jackson,  Dashyant Dhanak,  Robert A Copeland,  Kurt R Auger
Affiliations

Affiliation

  • 1 Department of Enzymology and Mechanistic Pharmacology, Oncology CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. lusong.luo@gsk.com
PMID: 17922005 DOI: 10.1038/nchembio.2007.34
Abstract

The mitotic Kinesin KSP (Kinesin spindle protein, or Eg5) has an essential role in centrosome separation and formation of the bipolar mitotic spindle. Its exclusive involvement in the mitotic spindle of proliferating cells presents an opportunity for developing new Anticancer agents with reduced side effects relative to antimitotics that target tubulin. Ispinesib is an allosteric small-molecule KSP inhibitor in phase 2 clinical trials. Mutations that attenuate ispinesib binding to KSP have been identified, which highlights the need for inhibitors that target different binding sites. We describe a new class of selective KSP inhibitors that are active against ispinesib-resistant forms of KSP. These ATP-competitive KSP inhibitors do not bind in the nucleotide binding pocket. Cumulative data from generation of resistant cells, site-directed mutagenesis and photo-affinity labeling suggest that they compete with ATP binding via a novel allosteric mechanism.

Figures
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