title: Discovery of potent KIFC1 inhibitors using a method of integrated high-throughput synthesis and screening.
abstract: KIFC1 (HSET), a member of the kinesin-14 family of motor proteins, plays an essential role in centrosomal bundling in cancer cells, but its function is not required for normal diploid cell division. To explore the potential of KIFC1 as a therapeutic target for human cancers, a series of potent KIFC1 inhibitors featuring a phenylalanine scaffold was developed from hits identified through high-throughput screening (HTS). Optimization of the initial hits combined both design-synthesis-test cycles and an integrated high-throughput synthesis and biochemical screening method. An important aspect of this integrated method was the utilization of DMSO stock solutions of compounds registered in the corporate compound collection as synthetic reactants. Using this method, over 1500 compounds selected for structural diversity were quickly assembled in assay-ready 384-well plates and were directly tested after the necessary dilutions. Our efforts led to the discovery of a potent KIFC1 inhibitor, AZ82, which demonstrated the desired centrosome declustering mode of action in cell studies.
authors.affiliation: Oncology Innovative Medicine Unit, AstraZeneca R&D Boston , 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Lamb
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Hennessy
authors.forename: Gurmit
authors.initials: G
authors.lastname: Grewal
authors.forename: Li
authors.initials: L
authors.lastname: Sha
authors.forename: Mark
authors.initials: M
authors.lastname: Zambrowski
authors.forename: Michael H
authors.initials: MH
authors.lastname: Block
authors.forename: James E
authors.initials: JE
authors.lastname: Dowling
authors.forename: Nancy
authors.initials: N
authors.lastname: Su
authors.forename: Jiaquan
authors.initials: J
authors.lastname: Wu
authors.forename: Tracy
authors.initials: T
authors.lastname: Deegan
authors.forename: Keith
authors.initials: K
authors.lastname: Mikule
authors.forename: Wenxian
authors.initials: W
authors.lastname: Wang
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Kaspera
authors.forename: Claudio
authors.initials: C
authors.lastname: Chuaqui
authors.forename: Huawei
authors.initials: H
authors.lastname: Chen
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D006367:HeLa Cells; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D016547:Kinesins / Q000037:antagonists & inhibitors*; D051379:Mice; D010649:Phenylalanine / Q000031:analogs & derivatives; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C000595393:5-methyl-N-(1-oxo-1-(pyrrolidin-3-ylamino)-3-(6-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)propan-2-yl)-4-propylthiophene-2-carboxamide; C486566:KIFC1 protein, human; D011725:Pyridines; D010649:Phenylalanine; D016547:Kinesins; D000409:Alanine