title: Discovery of novel spiro 1,3,4-thiadiazolines as potent, orally bioavailable and brain penetrant KSP inhibitors.
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.
authors: Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Electronic address: umar.faruk.mansoor@merck.com.
authors: Umar Faruk
authors: UF
authors: Mansoor
authors: Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors: Angie R
authors: AR
authors: Angeles
authors: Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors: Chaoyang
authors: C
authors: Dai
authors: Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors: Liping
authors: L
authors: Yang
authors: Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors: Dilrukshi
authors: D
authors: Vitharana
authors: Department of Cellular Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Andrea D
authors: AD
authors: Basso
authors: Department of Cellular Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Kimberly
authors: K
authors: Gray
authors: Department of Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Huadong
authors: H
authors: Tang
authors: Department of Cellular Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Ming
authors: M
authors: Liu
authors: Department of Cellular Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Lianzhu
authors: L
authors: Liang
authors: Department of Cellular Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.
authors: Omaira
authors: O
authors: Allbritton
authors: Department of Chemistry, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors: M Arshad
authors: MA
authors: Siddiqui
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004285:Dogs; D055808:Drug Discovery; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D010539:Permeability; D010880:Piperidines / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013871:Thiones / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: C530952:4-(2,5-difluorophenyl)-N-(3-fluoro-1-methylpiperidin-4-yl)-2-(hydroxymethyl)-N-methyl-2-phenyl-2,5-dihydro-1H-pyrrole-1-carboxamide; D000970:Antineoplastic Agents; D015415:Biomarkers; D006657:Histones; C470243:KIF11 protein, human; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; D013141:Spiro Compounds; D013830:Thiadiazoles; D013871:Thiones; D050257:Tubulin Modulators; C400223:monastrol; D016547:Kinesins
keywords: 1,3,4-Thiadiazolines; Anti-proliferation; Inhibitor; Kinesin spindle protein; Spirocycles