1. Academic Validation
  2. Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase

Discovery of GSK1070916, a potent and selective inhibitor of Aurora B/C kinase

  • J Med Chem. 2010 May 27;53(10):3973-4001. doi: 10.1021/jm901870q.
Nicholas D Adams 1 Jerry L Adams Joelle L Burgess Amita M Chaudhari Robert A Copeland Carla A Donatelli David H Drewry Kelly E Fisher Toshihiro Hamajima Mary Ann Hardwicke William F Huffman Kristin K Koretke-Brown Zhihong V Lai Octerloney B McDonald Hiroko Nakamura Ken A Newlander Catherine A Oleykowski Cynthia A Parrish Denis R Patrick Ramona Plant Martha A Sarpong Kosuke Sasaki Stanley J Schmidt Domingos J Silva David Sutton Jun Tang Christine S Thompson Peter J Tummino Jamin C Wang Hong Xiang Jingsong Yang Dashyant Dhanak
Affiliations

Affiliation

  • 1 Cancer Research, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426, USA. nicholas.d.adams@gsk.com
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.

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