Friday, April 17, 2015

Drugs in Clinical Pipeline: Abexinostat

Abexinostat [3-(dimethylaminomethyl)-N-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1-benzofuran-2-carboxamide] is a novel, second-generation phenyl hydroxamic acid-based, orally bioavailable HDAC inhibitor that has shown to have in vitro and in vivo activity  against a broad array of cancers, including hematopoietic malignancies and bone and soft-tissue sarcomas. Abexinostat inhibited pure recombinant HDAC1 with a Ki of 0.007 micromol/L, and also inhibited the other HDAC isozymes HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with Abexinostat resulted in the accumulation of acetylated histone and acetylated tubulin, resulting in an inhibition of tumor cell growth and the induction of apoptosis [1]. Abexinostat is being developed by Pharmacyclics Inc.

Common Name: Abexinostat
Synonyms: CRA-024781; CRA 024781; CRA024781; PCI-24781; PCI24781; PCI 24781
IUPAC Name: 3-(dimethylaminomethyl)-N-[2-[4-(hydroxycarbamoyl)phenoxy]ethyl]-1-benzofuran-2-carboxamide
CAS Number: 783355-60-2; 783356-67-2 (hydrochloride)
Mechanism of Action: HDAC Inhibitor; Histone Deacetylase Inhibitor
Indication: Various Cancers
Development Stage: Phase II

Company: Pharmacyclics Inc

It has also shown good tolerability and activity in Phase I and II clinical trials against lymphoma, as well as against solid tumors in Phase-I trials. Additionally, it acts as a potent radiosensitizing agent and is synergistic with cytotoxic chemotherapy, such as doxorubicin in preclinical models [2].

1. Buggy, J. J.; et. al. CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo. Mol Cancer Ther 2006, 5(5), 1309-1317.
2. Sholler, G. S.; et. al. PCI-24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma. J Cancer Ther Res 2013, 2, 21.