2. Academic Validation
  3. Hit to lead account of the discovery of a new class of inhibitors of Pim kinases and crystallographic studies revealing an unusual kinase binding mode

Hit to lead account of the discovery of a new class of inhibitors of Pim kinases and crystallographic studies revealing an unusual kinase binding mode

  • J Med Chem. 2009 Apr 9;52(7):1814-27. doi: 10.1021/jm801242y.
Kevin Qian 1,  Lian Wang,  Charles L Cywin,  Bennett T Farmer 2nd,  Eugene Hickey,  Carol Homon,  Scott Jakes,  Mohammed A Kashem,  George Lee,  Scott Leonard,  Jun Li,  Ronald Magboo,  Wang Mao,  Edward Pack,  Charlene Peng,  Anthony Prokopowicz 3rd,  Morgan Welzel,  John Wolak,  Tina Morwick
Affiliations

Affiliation

  • 1 Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, Connecticut 06801-0368, USA.
PMID: 19256503 DOI: 10.1021/jm801242y
Abstract

A series of inhibitors of Pim-2 kinase identified by high-throughput screening is described. Details of the hit validation and lead generation process and structure-activity relationship (SAR) studies are presented. Disclosure of an unconventional binding mode for 1, as revealed by X-ray crystallography using the highly homologous Pim-1 protein, is also presented, and observed binding features are shown to correlate with the Pim-2 SAR. While highly selective within the kinase family, the series shows similar potency for both Pim-1 and Pim-2, which was expected on the basis of homology, but unusual in LIGHT of reports in the literature documenting a bias for Pim-1. A rationale for these observations based on Pim-1 and Pim-2 K(M(ATP)) values is suggested. Some interesting cross reactivity with casein kinase-2 was also identified, and structural features which may contribute to the association are discussed.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-160006
    Pim-2 Inhibitor
    Pim