title: Design, synthesis, and biological evaluation of an allosteric inhibitor of HSET that targets cancer cells with supernumerary centrosomes.
abstract: Centrosomes associate with spindle poles; thus, the presence of two centrosomes promotes bipolar spindle assembly in normal cells. Cancer cells often contain supernumerary centrosomes, and to avoid multipolar mitosis and cell death, these are clustered into two poles by the microtubule motor protein HSET. We report the discovery of an allosteric inhibitor of HSET, CW069, which we designed using a methodology on an interface of chemistry and biology. Using this approach, we explored millions of compounds in silico and utilized convergent syntheses. Only compound CW069 showed marked activity against HSET in vitro. The inhibitor induced multipolar mitoses only in cells containing supernumerary centrosomes. CW069 therefore constitutes a valuable tool for probing HSET function and, by reducing the growth of cells containing supernumerary centrosomes, paves the way for new cancer therapeutics.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK.
authors.forename: Ciorsdaidh A
authors.initials: CA
authors.lastname: Watts
authors.forename: Frances M
authors.initials: FM
authors.lastname: Richards
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
authors.forename: Oliver
authors.initials: O
authors.lastname: Korb
authors.forename: Oliver
authors.initials: O
authors.lastname: Kern
authors.forename: Michelle
authors.initials: M
authors.lastname: Riddick
authors.forename: Paul
authors.initials: P
authors.lastname: Owen
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Myers
authors.forename: Jordan
authors.initials: J
authors.lastname: Raff
authors.forename: Fanni
authors.initials: F
authors.lastname: Gergely
authors.forename: Duncan I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: Steven V
authors.initials: SV
authors.lastname: Ley
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018385:Centrosome / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D061986:MCF-7 Cells; D008958:Models, Molecular; D015394:Molecular Structure; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C000593979:CW069 compound; D004791:Enzyme Inhibitors; D062367:ortho-Aminobenzoates; D010649:Phenylalanine; D016547:Kinesins