title: Discovery of (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), a kinesin spindle protein inhibitor and potential anticancer agent.
abstract: Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.
authors: Cancer & Infection Research Area, AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. Maria-Elena.Theoclitou@astrazeneca.com
authors: Maria-Elena
authors: ME
authors: Theoclitou
authors: Brian
authors: B
authors: Aquila
authors: Michael H
authors: MH
authors: Block
authors: Patrick J
authors: PJ
authors: Brassil
authors: Lillian
authors: L
authors: Castriotta
authors: Erin
authors: E
authors: Code
authors: Michael P
authors: MP
authors: Collins
authors: Audrey M
authors: AM
authors: Davies
authors: Tracy
authors: T
authors: Deegan
authors: Jayachandran
authors: J
authors: Ezhuthachan
authors: Sandra
authors: S
authors: Filla
authors: Ellen
authors: E
authors: Freed
authors: Haiqing
authors: H
authors: Hu
authors: Dennis
authors: D
authors: Huszar
authors: Muthusamy
authors: M
authors: Jayaraman
authors: Deborah
authors: D
authors: Lawson
authors: Paula M
authors: PM
authors: Lewis
authors: Murali V P
authors: MV
authors: Nadella
authors: Vibha
authors: V
authors: Oza
authors: Maniyan
authors: M
authors: Padmanilayam
authors: Timothy
authors: T
authors: Pontz
authors: Lucienne
authors: L
authors: Ronco
authors: Daniel
authors: D
authors: Russell
authors: David
authors: D
authors: Whitston
authors: Xiaolan
authors: X
authors: Zheng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D011485:Protein Binding; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D001798:Blood Proteins; C470243:KIF11 protein, human; C568512:N-(3-aminopropyl)-N-(1-(5-benzyl-3-methyl-4-oxo-(1,2)thiazolo(5,4-d)pyrimidin-6-yl)-2-methylpropyl)-4-methylbenzamide; D011744:Pyrimidinones; D016547:Kinesins