Saturday, April 18, 2015

Drugs in Clinical Pipeline: Rocilinostat

Rocilinostat [2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide] is novel, orally bioavailable, selective and specific inhibitor of histone deacetylase 6 (HDAC6) with potential antineoplastic activity. 

Rocilinostat, a hydroxamic acid derivative demonstrated potent and selective inhibitory activity against HDAC6, with an enzymatic IC50 value of ~ 5 nM. Rocilinostat is 12-, 10-, and 11-fold less active against HDAC1, HDAC2, and HDAC3 (class I HDACs, IC50 = 58, 48 and 51 nM), respectively. Rocilinostat has minimal activity (IC50 greater than 1 µM) against HDAC4, HDAC5, HDAC7, HDAC9, HDAC11, Sirtuin1, and Sirtuin2, and has slight activity against HDAC8 (IC50 = 0.1 µM) [1].

Acetylon Pharmaceuticals is developing Rocilinostat and it is evaluating Ricolinostat in several clinical studies for the treatment of multiple myeloma and lymphoma. Rocilinostat was chosen from several lead candidates because of its properties that favor drug development. These criteria included at least 10-fold selectivity against HDAC6 compared with class 1 HDACs, minimal activity against other HDAC enzymes, and a lack of significant activity against an extensive panel of receptors, transporters, and enzymes, including kinases. Additional criteria included suitable oral bioavailability in rodents and nonrodents, cellular permeability, metabolic stability, and an appropriate in vitro safety profile with minimal drug-drug interaction, minimal potential for QTc prolongation (hERG channel), and no significant genotoxic signal in mammalian cells. Further, experimental data show that Rocilinostat was less toxic against PBMCs and T cells isolated from healthy volunteers compared with SAHA.

The activity of Rocilinostat is as follows:

IC50 (HDAC6 enzyme assay) = 4.7 nM
IC50 (HDAC2 enzyme assay) = 48 nM
IC50 (HDAC3 enzyme assay) = 51 nM
IC50 (HDAC1 enzyme assay) = 58 nM
IC50 (HDAC8 enzyme assay) = 100 nM
IC50 (HDAC7 enzyme assay) = 1400 nM
IC50 (HDAC4 enzyme assay) = 7000 nM
IC50 (HDAC5 enzyme assay) = 5000 nM
IC50 (HDAC9 enzyme assay) = greater than 10 uM
IC50 (HDAC11 enzyme assay) = greater than 10 uM
IC50 (Sirtuin 1 enzyme assay) = greater than 10 uM
IC50 (Sirtuin 2 enzyme assay) = greater than 10 uM

Common Name: Rocilinostat
Synonyms: ACY-1215; ACY-1215; ACY-1215
IUPAC Name: 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide
CAS Number: 1316214-52-4
Mechanism of Action: HDAC Inhibitor; HDAC6 Inhibitor; Histone Deacetylase 6 Inhibitor
Indication: Multiple Myeloma and Lymphoma
Development Stage: Phase I/II
Company: Acetylon Pharmaceuticals

Pre-Clinical Characterisation

Unlike all other HDACs, HDAC6 has substrate specificity for α-tubulin because of its α-tubulin deacetylase domain. Rocilinostat induces potent acetylation of α-tubulin at very low doses and triggers acetylation of lysine on histone H3 and histone H4 only at higher doses, confirming its specific inhibitory effect on HDAC6 activity. This specific inhibition was also observed in patient multiple myeloma (MM) cells, in which Rocilinostat increased acetylated a-tubulin after 4 hours of treatment. However, after prolonged exposure or with significantly higher concentrations of Rocilinostat, it is possible that the low level of class 1 HDACs (HDAC1, HDAC2, and HDAC3) inhibition by Rocilinostat may also contribute to MM cell cytotoxicity and to potent inhibition of HDAC6.

1. Santo, L.; et. al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 2012, 119(11), 2579-2589.