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.