Details

Autor(en) / Beteiligte

• Parrish, Cynthia A
• Adams, Nicholas D
• Auger, Kurt R
• Burgess, Joelle L
• Carson, Jeffrey D
• Chaudhari, Amita M
• Copeland, Robert A
• Diamond, Melody A
• Donatelli, Carla A
• Duffy, Kevin J
• Faucette, Leo F
• Finer, Jeffrey T
• Huffman, William F
• Hugger, Erin D
• Jackson, Jeffrey R
• Knight, Steven D
• Luo, Lusong
• Moore, Michael L
• Newlander, Ken A
• Ridgers, Lance H
• Sakowicz, Roman
• Shaw, Antony N
• Sung, Chiu-Mei M
• Sutton, David
• Wood, Kenneth W
• Zhang, Shu-Yun
• Zimmerman, Michael N
• Dhanak, Dashyant

Titel

Novel ATP-Competitive Kinesin Spindle Protein Inhibitors

Ist Teil von

• Journal of medicinal chemistry, 2007-10, Vol.50 (20), p.4939-4952

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.