Discovery of highly potent and selective pan-Aurora kinase inhibitors with enhanced in vivo antitumor therapeutic index

Gang Liu; Sunny Abraham; Lan Tran; Troy D Vickers; Shimin Xu; Michael J Hadd; Sheena Quiambao; Mark W Holladay; Helen Hua; Julia M Ford Pulido; Ruwanthi N Gunawardane; Mindy I Davis; Shawn R Eichelberger; Julius L Apuy; Dana Gitnick; Michael F Gardner; Joyce James; Mike A Breider; Barbara Belli; Robert C Armstrong; Daniel K Treiber

doi:10.1021/jm201702g

Discovery of highly potent and selective pan-Aurora kinase inhibitors with enhanced in vivo antitumor therapeutic index

J Med Chem. 2012 Apr 12;55(7):3250-60. doi: 10.1021/jm201702g. Epub 2012 Mar 14.

Affiliation

¹ Department of Medicinal Chemistry, Ambit Biosciences Corporation, 4215 Sorrento Valley Boulevard, San Diego, California 92121, USA. gliu@ambitbio.com

PMID: 22380736
DOI: 10.1021/jm201702g

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.

MeSH terms

Acetanilides / chemical synthesis*
Acetanilides / pharmacokinetics
Acetanilides / pharmacology
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Aurora Kinase A
Aurora Kinases
Catalytic Domain
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Histones / metabolism
Humans
Models, Molecular
Neoplasm Transplantation
Phosphorylation
Protein Binding
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Rats
Rats, Nude
Rats, Sprague-Dawley
Stereoisomerism
Structure-Activity Relationship
Transplantation, Heterologous
Triazines / chemical synthesis*
Triazines / pharmacokinetics
Triazines / pharmacology

Substances

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
Acetanilides
Antineoplastic Agents
Histones
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
Triazines
Aurka protein, rat
Aurora Kinase A
Aurora Kinases
Protein Serine-Threonine Kinases