Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site

  • Chem Biol. 2011 Feb 25;18(2):177-86. doi: 10.1016/j.chembiol.2010.12.013.
Jingsong Yang  1 ,  Nino Campobasso ,  Mangatt P Biju ,  Kelly Fisher ,  Xiao-Qing Pan ,  Josh Cottom ,  Sarah Galbraith ,  Thau Ho ,  Hong Zhang ,  Xuan Hong ,  Paris Ward ,  Glenn Hofmann ,  Brett Siegfried ,  Francesca Zappacosta ,  Yoshiaki Washio ,  Ping Cao ,  Junya Qu ,  Sophie Bertrand ,  Da-Yuan Wang ,  Martha S Head ,  Hu Li ,  Sheri Moores ,  Zhihong Lai ,  Kyung Johanson ,  George Burton ,  Connie Erickson-Miller ,  Graham Simpson ,  Peter Tummino ,  Robert A Copeland ,  Allen Oliff
Affiliations
  • 1. Oncology Research and Development, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. [email protected]
PMID: 21338916 DOI: 10.1016/j.chembiol.2010.12.013
Abstract

c-Abl kinase activity is regulated by a unique mechanism involving the formation of an autoinhibited conformation in which the N-terminal myristoyl group binds intramolecularly to the myristoyl binding site on the kinase domain and induces the bending of the αI helix that creates a docking surface for the SH2 domain. Here, we report a small-molecule c-Abl activator, DPH, that displays potent enzymatic and cellular activity in stimulating c-Abl activation. Structural analyses indicate that DPH binds to the myristoyl binding site and prevents the formation of the bent conformation of the αI helix through steric hindrance, a mode of action distinct from the previously identified allosteric c-Abl inhibitor, GNF-2, that also binds to the myristoyl binding site. DPH represents the first cell-permeable, small-molecule tool compound for c-Abl activation.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12070
    DPH
    99.38%, Bcr-Abl Activator
    target: Bcr-Abl
    Research Areas: Cancer