title: Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase.
abstract: The Aurora kinases play critical roles in the regulation of mitosis and are frequently overexpressed or amplified in human tumors. Selective inhibitors may provide a new therapy for the treatment of tumors with Aurora kinase amplification. Herein we describe our lead optimization efforts within a 7-azaindole-based series culminating in the identification of GSK1070916 (17k). Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity. Compound 17k is a potent and selective ATP-competitive inhibitor of Aurora B and C with K(i)* values of 0.38 +/- 0.29 and 1.5 +/- 0.4 nM, respectively, and is >250-fold selective over Aurora A. Biochemical characterization revealed that compound 17k has an extremely slow dissociation half-life from Aurora B (>480 min), distinguishing it from clinical compounds 1 and 2. In vitro treatment of A549 human lung cancer cells with compound 17k results in a potent antiproliferative effect (EC(50) = 7 nM). Intraperitoneal administration of 17k in mice bearing human tumor xenografts leads to inhibition of histone H3 phosphorylation at serine 10 in human colon cancer (Colo205) and tumor regression in human leukemia (HL-60). Compound 17k is being progressed to human clinical trials.
authors.affiliation: Cancer Research, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. nicholas.d.adams@gsk.com
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Adams
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Adams
authors.forename: Joelle L
authors.initials: JL
authors.lastname: Burgess
authors.forename: Amita M
authors.initials: AM
authors.lastname: Chaudhari
authors.forename: Robert A
authors.initials: RA
authors.lastname: Copeland
authors.forename: Carla A
authors.initials: CA
authors.lastname: Donatelli
authors.forename: David H
authors.initials: DH
authors.lastname: Drewry
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Fisher
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Hamajima
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Hardwicke
authors.forename: William F
authors.initials: WF
authors.lastname: Huffman
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Koretke-Brown
authors.forename: Zhihong V
authors.initials: ZV
authors.lastname: Lai
authors.forename: Octerloney B
authors.initials: OB
authors.lastname: McDonald
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakamura
authors.forename: Ken A
authors.initials: KA
authors.lastname: Newlander
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Oleykowski
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Parrish
authors.forename: Denis R
authors.initials: DR
authors.lastname: Patrick
authors.forename: Ramona
authors.initials: R
authors.lastname: Plant
authors.forename: Martha A
authors.initials: MA
authors.lastname: Sarpong
authors.forename: Kosuke
authors.initials: K
authors.lastname: Sasaki
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Schmidt
authors.forename: Domingos J
authors.initials: DJ
authors.lastname: Silva
authors.forename: David
authors.initials: D
authors.lastname: Sutton
authors.forename: Jun
authors.initials: J
authors.lastname: Tang
authors.forename: Christine S
authors.initials: CS
authors.lastname: Thompson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tummino
authors.forename: Jamin C
authors.initials: JC
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Xiang
authors.forename: Jingsong
authors.initials: J
authors.lastname: Yang
authors.forename: Dashyant
authors.initials: D
authors.lastname: Dhanak
mesh_terms: D000818:Animals; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006657:Histones / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D001372:Aza Compounds; C544308:GSK 1070916; D006657:Histones; D007211:Indoles; C576921:AURKB protein, human; C576918:Aurka protein, mouse; C576924:Aurkb protein, mouse; D064096:Aurora Kinase A; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases