piperidines and monastrol

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.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Biomarkers; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Dogs; Drug Discovery; HCT116 Cells; Histones; Humans; Kinesins; Male; Mice; Permeability; Piperidines; Pyrimidines; Pyrroles; Rats; Spiro Compounds; Thiadiazoles; Thiones; Tubulin Modulators; Xenograft Model Antitumor Assays