title: Discovery of highly potent and selective pan-Aurora kinase inhibitors with enhanced in vivo antitumor therapeutic index.
abstract: Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis. Currently a number of Aurora kinase inhibitors with different isoform selectivities are being evaluated in the clinic. Herein we report the discovery and characterization of 21c (AC014) and 21i (AC081), two structurally novel, potent, kinome-selective pan-Aurora inhibitors. In the human colon cancer cell line HCT-116, both compounds potently inhibit histone H3 phosphorylation and cell proliferation while inducing 8N polyploidy. Both compounds administered intravenously on intermittent schedules displayed potent and durable antitumor activity in a nude rat HCT-116 tumor xenograft model and exhibited good in vivo tolerability. Taken together, these data support further development of both 21c and 21i as potential therapeutic agents for the treatment of solid tumors and hematological malignancies.
authors.affiliation: Department of Medicinal Chemistry, Ambit Biosciences Corporation, 4215 Sorrento Valley Boulevard, San Diego, California 92121, USA. gliu@ambitbio.com
authors.forename: Gang
authors.initials: G
authors.lastname: Liu
authors.forename: Sunny
authors.initials: S
authors.lastname: Abraham
authors.forename: Lan
authors.initials: L
authors.lastname: Tran
authors.forename: Troy D
authors.initials: TD
authors.lastname: Vickers
authors.forename: Shimin
authors.initials: S
authors.lastname: Xu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hadd
authors.forename: Sheena
authors.initials: S
authors.lastname: Quiambao
authors.forename: Mark W
authors.initials: MW
authors.lastname: Holladay
authors.forename: Helen
authors.initials: H
authors.lastname: Hua
authors.forename: Julia M
authors.initials: JM
authors.lastname: Ford Pulido
authors.forename: Ruwanthi N
authors.initials: RN
authors.lastname: Gunawardane
authors.forename: Mindy I
authors.initials: MI
authors.lastname: Davis
authors.forename: Shawn R
authors.initials: SR
authors.lastname: Eichelberger
authors.forename: Julius L
authors.initials: JL
authors.lastname: Apuy
authors.forename: Dana
authors.initials: D
authors.lastname: Gitnick
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gardner
authors.forename: Joyce
authors.initials: J
authors.lastname: James
authors.forename: Mike A
authors.initials: MA
authors.lastname: Breider
authors.forename: Barbara
authors.initials: B
authors.lastname: Belli
authors.forename: Robert C
authors.initials: RC
authors.lastname: Armstrong
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Treiber
mesh_terms: D000083:Acetanilides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D064096:Aurora Kinase A; D064127:Aurora Kinases; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006657:Histones / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011923:Rats, Nude; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D014227:Triazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C574644:2-(3-(3,3-difluoropyrrolidine-1-carbonyl)pyrrolidin-1-yl)-N-(4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo(2,1-f)(1,2,4)triazin-2-yl)thio)phenyl)acetamide; D000083:Acetanilides; D000970:Antineoplastic Agents; D006657:Histones; C574645:N-cyclopentyl-1-(2-((4-((4-((5-methyl-1H-pyrazol-3-yl)amino)pyrrolo(2,1-f)(1,2,4)triazin-2-yl)thio)phenyl)amino)-2-oxoethyl)pyrrolidine-3-carboxamide; D014227:Triazines; C576920:Aurka protein, rat; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases