Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 23, Issue 10, Pages 2424-2434Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2015.03.052
Keywords
Kinesin spindle protein; Inhibitor; Anti-proliferation; Spirocycles; 1,3,4-Thiadiazolines
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Kinesin spindle protein (KSP) is a mitotic kinesin that is expressed only in proliferating cells and plays a key role in spindle pole separation, formation of a bipolar mitotic spindle, as well as centrosome separation and maturation. Inhibition of KSP has the potential to provide anti-tumor activity while avoiding peripheral neuropathy associated with some microtubule-targeted drugs. Based on MK-0731 and related heterocyclic compounds targeting the KSP monastrol binding site, structurally constrained spiro-cyclic KSP inhibitors were designed. In particular, rapid evaluation and optimization of the novel spiro 1,3,4-thiadiazolines resulted in a series of potent KSP inhibitors demonstrating mechanism based activities in cells, including induction of the mitotic marker phospho-histone H3 and induction of monaster spindle formation. Further optimization of the pharmacokinetic (PK) properties afforded MK-8267 as a potent, orally bioavailable and brain penetrant KSP inhibitor which showed anti-tumor activity in preclinical xenograft models. (C) 2015 Elsevier Ltd. All rights reserved.
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