Discovery of novel spiro 1, 3, 4-thiadiazolines as potent, orally bioavailable and brain penetrant KSP inhibitors. Issue 10 (15th May 2015)

• Record Type: Journal Article
• Authors: Mansoor, Umar Faruk; Angeles, Angie R.; Dai, Chaoyang; Yang, Liping; Vitharana, Dilrukshi; Basso, Andrea D.; Gray, Kimberly; Tang, Huadong; Liu, Ming; Liang, Lianzhu; Allbritton, Omaira; Siddiqui, M. Arshad
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 10(2015)
• Page Start: 2424
• Page End: 2434
• Publication Date: 2015-05-15
• Subjects: Kinesin spindle protein -- Inhibitor -- Anti-proliferation -- Spirocycles -- 1, 3, 4-Thiadiazolines; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.03.052
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 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.