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Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192

Boissinot, M; Inman, M; Hempshall, A; James, S.R; Gill, J.H; Selby, P; Bowen, D.T; Grigg, R.E; Cockerill, P.N

Authors

M Boissinot

M Inman

A Hempshall

S.R James

J.H Gill

P Selby

D.T Bowen

R.E Grigg

P.N Cockerill



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.

Citation

Boissinot, M., Inman, M., Hempshall, A., James, S., Gill, J., Selby, P., …Cockerill, P. (2012). Induction of differentiation and apoptosis in leukaemic cell lines by the novel benzamide family histone deacetylase 2 and 3 inhibitor MI-192. Leukemia Research, 36(10), 1304-1310. https://doi.org/10.1016/j.leukres.2012.07.002

Journal Article Type Article
Publication Date Oct 1, 2012
Deposit Date Dec 21, 2012
Journal Leukemia Research
Print ISSN 0145-2126
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 36
Issue 10
Pages 1304-1310
DOI https://doi.org/10.1016/j.leukres.2012.07.002
Keywords HDAC inhibitor, Benzamide, MI-192, Differentiation, Apoptosis.
Publisher URL http://10.1016/j.leukres.2012.07.002