SCH 2047069, a novel oral kinesin spindle protein inhibitor, shows single-agent antitumor activity and enhances the efficacy of chemotherapeutics.
Kinesin spindle protein (KSP) is a mitotic kinesin required for the formation of the bipolar mitotic spindle, and inhibition of this motor protein results in mitotic arrest and cell death. KSP inhibitors show preclinical antitumor activity and are currently undergoing testing in clinical trials. These agents have been dosed intravenously using various dosing schedules. We sought to identify a KSP inhibitor that could be delivered orally and thus provide convenience of dosing as well as the ability to achieve more continuous exposure via the use of dose-dense administration. We discovered SCH 2047069, a potent KSP inhibitor with oral bioavailability across species and the ability to cross the blood-brain barrier. The compound induces mitotic arrest characterized by a monaster spindle and is associated with an increase in histone H3 and mitotic protein monoclonal 2 phosphorylation both in vitro and in vivo. SCH 2047069 showed antitumor activity in a variety of preclinical models as a single agent and in combination with paclitaxel, gemcitabine, or vincristine.
Department of Oncology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07093, USA. andrea.basso@merck.com
Andrea D
AD
Basso
Ming
M
Liu
Chaoyang
C
Dai
Kimberly
K
Gray
Lissette
L
Nale
Seema
S
Tevar
Suining
S
Lee
Lianzhu
L
Liang
Abdul
A
Ponery
Bohdan
B
Yaremko
Elizabeth
E
Smith
Huadong
H
Tang
Payal R
PR
Sheth
M Arshad
MA
Siddiqui
Daniel J
DJ
Hicklin
Paul
P
Kirschmeier
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D001578:Benzopyrans / Q000008:administration & dosage* / Q000494:pharmacology*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D045325:HCT116 Cells; D000882:Haplorhini; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D013830:Thiadiazoles / Q000008:administration & dosage* / Q000494:pharmacology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001578:Benzopyrans; C470243:KIF11 protein, human; C556170:SCH 2047069; D013830:Thiadiazoles; D016547:Kinesins