2. Academic Validation
  3. Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles

Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles

  • J Med Chem. 2005 Mar 24;48(6):1873-85. doi: 10.1021/jm0495935.
Kristen L Arienti 1,  Anders Brunmark,  Frank U Axe,  Kelly McClure,  Alice Lee,  Jon Blevitt,  Danielle K Neff,  Liming Huang,  Shelby Crawford,  Chennagiri R Pandit,  Lars Karlsson,  J Guy Breitenbucher
Affiliations

Affiliation

  • 1 Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.
PMID: 15771432 DOI: 10.1021/jm0495935
Abstract

The discovery of a series of novel, potent, and highly selective inhibitors of the DNA damage control kinase Chk2 is disclosed. Here we report the first SAR study around inhibitors of this kinase. High-throughput screening of purified human Chk2 led to the identification of a novel series of 2-arylbenzimidazole inhibitors of the kinase. Optimization was facilitated using homology models of Chk2 and docking of inhibitors, leading to the highly potent 2-arylbenzimidazole 2h (IC(50) 15 nM). Compound 2h is an ATP-competitive inhibitor of Chk2 that dose dependently protects human CD4(+) and CD8(+) T-cells from Apoptosis due to ionizing radiation. This work suggests that a selective small molecule inhibitor of Chk2 could be a useful Adjuvant to radiotherapy, increasing the therapeutic window of such treatment.

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