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Milestone in the development of Histone Deacetylase Inhibitors

Milestone in the development of Histone Deacetylase Inhibitors


This alert is brought to you by LeadDiscovery and concerns today's announcement by Celera Genomics that clinical evaluation of their HDAC inhibitor CRA-024781 is about to commence. The press release is featured on today's edition of DailyUpdates-Oncology.
Last Updated: 27-Aug-2010

Special alert from DailyUpdates-Oncology: Milestone in the development of Histone Deacetylase Inhibitors

This alert is brought to you by LeadDiscovery and concerns Celera Genomics' July 14th today's announcement that clinical evaluation of their HDAC inhibitor CRA-024781 is about to commence. The press release is featured on today's edition of DailyUpdates-Oncology. Click here to access this bulletin or read our editorial below.

Editorial Comment

The field of histone deacetylase (HDACs) inhibition has recently started to move from a preclinical approach to one actively being investigated in the clinic  (for an in depth look at this field see LeadDiscovery's report Histone deacetylase inhibitors-Moving from the bench to a promising companion for classic and targeted cancer therapies). Two of the most advanced clinical candidates are Merck's SAHA and Gloucester Pharmaceuticals' FK288 (depsipeptide; FK901228).

Inhibition of the HDACs is able to promote a variety of different anti-cancer mechanisms including apoptosis, cell differentiation and cell cycle inhibition. In our recent report we conclude that as long as phase II data is in agreement with the promising earlier stage data already available then HDAC inhibitors could represent one of the next classes of promising anticancer agent to hit the market. On May 25th, 2005 Gloucester provided important information on FK288 as a single agent treatment. In their release Gloucester announced the first in a series of expected phase II data reporting efficacy in patients with peripheral T-cell lymphoma (see press release)

Today sees another milestone in the development of HDAC inhibitors with Celera Genomics announcing in a press release the advancement of its inhibitor, CRA-024781, into the clinic. Celera recently reported data at the American Association for Cancer Research meeting in April 2005, showing the efficacy of CRA-024781 as an HDAC inhibitor in xenograft cancer models. In today's release Celera announce the imminent initiation of phase I trials in patients with refractory solid malignancies.

Today's announcement is of considerable importance with data from the planed trial expected to provide further proof of concept to support the development of HDAC inhibitors. Moreover it is important to note that the planed study will recruit patients with solid tumors contrasting with the majority of clinical studies conducted to date which have focused on hematological malignancies. Perhaps of even greater interest however will be data from the next generation of HDAC inhibitors to emerge from Celera's pipeline. These inhibitors are expected to target HDAC8 following the company's success in solving the crystal structure of this enzyme in 2004.

Being able to target specific HDAC isoforms is likely to improve the therapeutic margin of this drug class however it has also forced the question of what is the optimal profile of HDAC isoform targets?  To date 11 HDAC isoforms have been identified. HDAC1 has been shown in a large number of studies to mediate cellular effects consistent with anticancer activity.  Hence selective inhibitors such as Schering's MS-27-275 (HDAC1 selective) may be expected to have advantages over SAHA and FK228 which are non-selective inhibitors are which are therefore at a greater risk of producing adverse effects.  Selective HDAC1 inhibition does not however appear to represent the optimal profile of activity; MethyGene have focused on using functional genomics to identify those HDACs that could play a major role in treating cancer and they have recently suggested that HDAC8 may be another appropriate target.  Indeed the company has reported that HDAC8 inhibition induces growth arrest and apoptosis in human cancer cells but not in normal cells. Developing dual HDAC1/HDAC8 inhibitors may therefore offer a useful approach and for this reason further information on Celera's next-generation inhibitors is eagerly awaited. 

Also anticipated is an expansion of the indications for the HDAC inhibitor class. In particular HDAC inhibitors are emerging as candidates for the treatment of inflammatory/autoimmune and neurodegenerative disorders and only yesterday DailyUpdates-Immunology & Inflammatory Disorders highlighted new research supporting the development of HDAC inhibitors as an approach to multiple sclerosis (click here for this channel of DailyUpdates). Together therefore the body of data underlying this area of biology continues to advance and hopefully these advances will soon delivery new therapeutic options to a significant number of patients.

Readers of this editorial may also be interested in the following reports: