title: Checkpoint kinase inhibitors: SAR and radioprotective properties of a series of 2-arylbenzimidazoles.
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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research and Development, L.L.C., 3210 Merryfield Row, San Diego, California 92121, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Arienti
authors.forename: Anders
authors.initials: A
authors.lastname: Brunmark
authors.forename: Frank U
authors.initials: FU
authors.lastname: Axe
authors.forename: Kelly
authors.initials: K
authors.lastname: McClure
authors.forename: Alice
authors.initials: A
authors.lastname: Lee
authors.forename: Jon
authors.initials: J
authors.lastname: Blevitt
authors.forename: Danielle K
authors.initials: DK
authors.lastname: Neff
authors.forename: Liming
authors.initials: L
authors.lastname: Huang
authors.forename: Shelby
authors.initials: S
authors.lastname: Crawford
authors.forename: Chennagiri R
authors.initials: CR
authors.lastname: Pandit
authors.forename: Lars
authors.initials: L
authors.lastname: Karlsson
authors.forename: J Guy
authors.initials: JG
authors.lastname: Breitenbucher
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000528:radiation effects; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000528:radiation effects; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D005720:Gamma Rays; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D010647:Phenyl Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011837:Radiation-Protective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: C500066:2-(4-(4-chlorophenoxy)phenyl)-1H-benzimidazole-5-carboxylic acid amide; D001562:Benzimidazoles; D010647:Phenyl Ethers; D011837:Radiation-Protective Agents; D000255:Adenosine Triphosphate; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases