title: MR22388, a novel anti-cancer agent with a strong FLT-3 ITD kinase affinity.
abstract: This work describes the study of the mechanism of action and spectrum of activity of MR22388, a novel anti-cancer agent belonging to the tripentone series. MR22388 is highly cytotoxic (within the nanomolar range) against numerous cancer cell lines and studies of its cytotoxicity mechanisms show that it is a weak inhibitor of the polymerization of tubulin and that it induces apoptosis via the MAP kinase pathways. Further MR22388 is a very strong inhibitor of several kinases including the tyrosine kinase FLT3-ITD. FLT3-ITD is a mutated form of the tyrosine kinase receptor (RTK) FLT3, resulting in the constitutive activation of the kinase, occurring in about 25% of normal karyotypes' Acute Myeloid Leukemia (AML) and is linked to a bad prognosis. Consecutively, MR22388 appears as a novel promising anticancer lead agent especially for AML therapy.
authors.affiliation: CERMN, UFR des Sciences Pharmaceutiques, UPRES EA 4258 - FR CNRS 3038 INC3M - SF 4206 ICORE, Université de Caen Basse-Normandie, Bd Becquerel, 14032 Caen cedex, France. christophe.rochais@unicaen.fr
authors.forename: Christophe
authors.initials: C
authors.lastname: Rochais
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.forename: Vittoria
authors.initials: V
authors.lastname: Perri
authors.forename: Marie
authors.initials: M
authors.lastname: Jouanne
authors.forename: Aurélien
authors.initials: A
authors.lastname: Lesnard
authors.forename: Sylvain
authors.initials: S
authors.lastname: Rault
authors.forename: Patrick
authors.initials: P
authors.lastname: Dallemagne
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011763:Pyrrolizidine Alkaloids / Q000494:pharmacology*; D020080:Tandem Repeat Sequences / Q000187:drug effects*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C483893:3-(3-hydroxy-4-methoxyphenyl)-8H-thieno(2,3-b)pyrrolizin-8-one; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011763:Pyrrolizidine Alkaloids; D014404:Tubulin; D050257:Tubulin Modulators; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3