title: Synthesis of Cis-fused pyran indolocarbazole derivatives that inhibit FLT3 kinase and the DNA damage kinase, checkpoint kinase 1.
abstract: Protein kinases are important enzymes in solid tumour and leukaemia pathologies. Their structures are well understood at the atomic level and their key role in the progression of certain cancers makes them valuable targets for anti-cancer therapy. Through medicinal chemical approaches, we developed an efficient preparative stereospecific synthesis of N12, N13 pyran-bridged indolocarbazoles that opens access to functional diversity within this previously challenging series. We focused upon the indolocarbazole class of chemical inhibitors, which includes S27888, an inhibitor we previously identified. We used biochemical and cell-based assays to identify small molecule inhibitors of Checkpoint kinase 1 (Chk1), a serine/threonine protein kinase that is activated when cancer cells are treated with genotoxic agents. These compounds show a promising inhibitory profile on Chk1. Furthermore, these compounds are active against FLT3, which is a tyrosine kinase that is frequently activated in human leukaemias. These data suggest that this chemical class may provide a source of therapeutic compounds for a broad range of human cancers.
authors: Institut de Recherches Servier, Medicinal Chemistry, Surenses, France. francoise.perronsierra@fr.netgrs.com
authors: Francoise M
authors: FM
authors: Perron-Sierra
authors: Nathalie
authors: N
authors: Kucharkzyk
authors: Celine
authors: C
authors: Boucley
authors: Christel
authors: C
authors: Guyard-Daumas
authors: Sophie
authors: S
authors: Sciberras
authors: Christine
authors: C
authors: Fouache
authors: Sabine
authors: S
authors: Plantier
authors: Aurelie
authors: A
authors: Studeny
authors: Celine
authors: C
authors: Bossard
authors: Patrick J
authors: PJ
authors: Casara
authors: Roy M
authors: RM
authors: Golsteyn
mesh_terms: D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011713:Pyran Copolymer / Q000737:chemistry* / Q000494:pharmacology; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D002227:Carbazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011713:Pyran Copolymer; D011494:Protein Kinases; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases