Patrick Angibaud

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

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.

5-imidazolyl-quinolinones, -quinazolinones and -benzo-azepinones as farnesyltransferase inhibitors.

The evaluation of structure-activity relationships associated with the modification of the R115777 quinolinone ring moiety displaying potent in vitro inhibiting activity is described.

Farnesyl Protein Transferase Inhibitors: Medicinal Chemistry, Molecular Mechanisms,and Progress in the Clinic

Over a decade has passed since the first report describing farnesyl protein transferase (FTase)and tetrapeptide inhibitors triggered a search for small-molecule inhibitors that could be developedas oral therapeutics. There are now several farnesyl protein inhibitors (FTIs) in various phases of clinicaldevelopment and at least two compounds have entered phase III. The published data suggest some disappointingactivity in the major solid tumors, with more promising activities emerging from studies of hematologicalmalignancies and glioblastoma. The current compounds emerged from various research strategies includingmodeling around the CAAX motif peptide substrate and the farnesyl pyrophosphate (FPP) substrate, as wellas high-throughput screening campaigns. The interaction of inhibitors in the active site of the FT enzymecan be accurately described thanks to the publication of the X-ray structure as well as excellent mechanisticwork. Published structure–activity data have revealed an interesting convergence on imidazole pharmacophores.The original hypothesis that drove development of FTIs anticipated therapy targeted specifically at thefarnesylated Ras oncoproteins and cancers with ras gene mutations. Asexperience with the newer potent FTIs grew, data emerged to suggest that multiple downstream effectors contributeto the antitumor activity of FTIs. The mechanism(s) of action of FTIs and the full therapeutic activityof the class remain areas of active investigation.