title: Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192.
abstract: Histone deacetylase inhibitors (HDACIs) are in advanced clinical development as cancer therapeutic agents. However, first generation HDACIs such as butyrate and valproate are simple short chain aliphatic compounds with moieties resembling acetyl groups, and have a broad spectrum of activity against HDACs. More complex second generation HDACIs undergoing clinical trials, such as the benzamide group compounds MS-275 and MGCD0103, are specific primarily for HDAC1 and HDAC2. To expand the repertoire of available HDACIs and HDAC specificities we created a novel benzamide-based compound named MI-192. When tested against purified recombinant HDACs, MI-192 had marked selectivity for the class I enzymes, HDAC2 and HDAC3. Screening in the NCI60 screen demonstrated that MI-192 had greatly enhanced efficacy against cells of leukaemic origin. When tested in culture against the acute myeloid leukaemic cell lines U937, HL60 and Kasumi-1, MI-192 induced differentiation and was cytotoxic through promotion of apoptosis. MI-192 therefore justifies further investigation and development as a potential therapeutic agent for use in leukaemia.
authors: Experimental Haematology, Leeds Institute of Molecular Medicine, University of Leeds, UK.
authors: Marjorie
authors: M
authors: Boissinot
authors: Martyn
authors: M
authors: Inman
authors: Aiden
authors: A
authors: Hempshall
authors: Sally R
authors: SR
authors: James
authors: Jason H
authors: JH
authors: Gill
authors: Peter
authors: P
authors: Selby
authors: David T
authors: DT
authors: Bowen
authors: Ronald
authors: R
authors: Grigg
authors: Peter N
authors: PN
authors: Cockerill
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D014407:Tumor Cells, Cultured; D000099186:Histone Deacetylase 3
chemical_list: D001549:Benzamides; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D000099186:Histone Deacetylase 3; C576022:MI-192