| Autor: |
Parrish CA; Department of Medicinal Chemistry, Oncology Center of Excellence for Drug Discovery, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. cynthia.a.parrish@gsk.com, Adams ND, Auger KR, Burgess JL, Carson JD, Chaudhari AM, Copeland RA, Diamond MA, Donatelli CA, Duffy KJ, Faucette LF, Finer JT, Huffman WF, Hugger ED, Jackson JR, Knight SD, Luo L, Moore ML, Newlander KA, Ridgers LH, Sakowicz R, Shaw AN, Sung CM, Sutton D, Wood KW, Zhang SY, Zimmerman MN, Dhanak D |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2007 Oct 04; Vol. 50 (20), pp. 4939-52. Date of Electronic Publication: 2007 Aug 29. |
| DOI: |
10.1021/jm070435y |
| Abstrakt: |
Kinesin spindle protein (KSP), an ATPase responsible for spindle pole separation during mitosis that is present only in proliferating cells, has become a novel and attractive anticancer target with potential for reduced side effects compared to currently available therapies. We report herein the discovery of the first known ATP-competitive inhibitors of KSP, which display a unique activity profile as compared to the known loop 5 (L5) allosteric KSP inhibitors that are currently under clinical evaluation. Optimization of this series led to the identification of biphenyl sulfamide 20, a potent KSP inhibitor with in vitro antiproliferative activity against human cells with either wild-type KSP (HCT116) or mutant KSP (HCT116 D130V). In a murine xenograft model with HCT116 D130V tumors, 20 showed significant antitumor activity following intraperitoneal dosing, providing in vivo proof-of-principle of the efficacy of an ATP-competitive KSP inhibitor versus tumors that are resistant to the other known KSP inhibitors. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
