title: 7-(4H-1,2,4-Triazol-3-yl)benzo[c][2,6]naphthyridines: a novel class of Pim kinase inhibitors with potent cell antiproliferative activity.
abstract: A novel class of pan-Pim kinase inhibitors was designed by modifying the CK2 inhibitor CX-4945. Introduction of a triazole or secondary amide functionality on the C-7 position and 2'-halogenoanilines on C-5 resulted in potent inhibitors of the Pim-1 and Pim-2 isoforms, with many analogs active at single digit nanomolar concentrations. The molecules inhibited the phosphorylation at Serine 112 of the apoptosis effector BAD, and had potent antiproliferative effects on the AML cell line MV-4-11 (IC(50) <30 nM). This work delivers an excellent lead-optimization platform for Pim targeting anticancer therapies.
authors: Cylene Pharmaceuticals, 5820 Nancy Ridge Drive, Suite 200, San Diego, CA 92121, USA. fpierre@cylenepharma.com
authors: Fabrice
authors: F
authors: Pierre
authors: Eric
authors: E
authors: Stefan
authors: Anne-Sophie
authors: AS
authors: Nédellec
authors: Marie-Claire
authors: MC
authors: Chevrel
authors: Collin F
authors: CF
authors: Regan
authors: Adam
authors: A
authors: Siddiqui-Jain
authors: Diwata
authors: D
authors: Macalino
authors: Nicole
authors: N
authors: Streiner
authors: Denis
authors: D
authors: Drygin
authors: Mustapha
authors: M
authors: Haddach
authors: Sean E
authors: SE
authors: O'Brien
authors: Kenna
authors: K
authors: Anderes
authors: David M
authors: DM
authors: Ryckman
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D009287:Naphthyridines / Q000737:chemistry* / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D009287:Naphthyridines; C490587:PIM2 protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D014230:Triazoles; C045575:1,2,4-triazole; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1