R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Autor: A Mariën, Manfred Jung, Patrick Rene Angibaud, Wim Floren, Michel Janicot, T. Geerts, K. Van Emelen, Boudewijn Janssens, Luc Andries, J. Van Dun, Peter King, J. Arts, L Janssen, Dana L. Johnson, R W Tuman
Rok vydání: 2007
Předmět:
Male
Cancer Research
Administration
Oral
Angiogenesis Inhibitors
Hydroxamic Acids
Histones
Rats
Sprague-Dawley
Mice
chemistry.chemical_compound
HDAC
Neoplasms
Tumor Cells
Cultured
JNJ-16241199
Sulfones
Enzyme Inhibitors
Promoter Regions
Genetic
Histone deacetylase inhibitor
Immunohistochemistry
Isoenzymes
Oncology
medicine.drug
Cyclin-Dependent Kinase Inhibitor p21
medicine.drug_class
small molecule
Mice
Nude
Antineoplastic Agents
Biology
HDAC inhibitor
In vivo
Cell Line
Tumor
Panobinostat
R306465
medicine
Animals
Humans
Vorinostat
Cell Proliferation
Dose-Response Relationship
Drug
Cell growth
HDAC6
Xenograft Model Antitumor Assays
anticancer agent
Rats
Enzyme Activation
Histone Deacetylase Inhibitors
Disease Models
Animal
chemistry
Acetylation
Cancer research
Histone deacetylase
Translational Therapeutics
Zdroj: British Journal of Cancer
ISSN: 1532-1827
0007-0920
DOI: 10.1038/sj.bjc.6604025
Popis: R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21waf1,cip1, a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.
Databáze: OpenAIRE
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