The Making of an HDAC Inhibitor
Research Models
James Duffy

The Making of an HDAC Inhibitor

How a small CRO's early discovery project led to the approval of Belinostat

We all appreciate the long, challenging, and all too often unsuccessful journey a drug takes from concept to approval. Indeed, current estimates for completion of the drug discovery and development process are well in excess of 10 years.

But when things work....well, it more than compensates for the challenging times.

Belinostat, approved last year for a rare form of lymphoma, was the first discovery project I worked on after joining the newly-formed Contract Research Organization (CRO) BioFocus in 1998. BioFocus is now part of Charles River Laboratories and employs 240 scientists, but in those days it only had around 15 staff and only offered chemistry services (synthetic and computational chemistry). This seems, and is, a long, long way from the integrated biology, chemistry and DMPK in vitro and in vivo capabilities that we now offer as part of Charles River Discovery Services.

The objective of the project was to identify inhibitors of a family of enzymes known as histone deacetylases (HDACs) that are associated with the control of processes leading to cell proliferation and differentiation. We were working with a biotech company called Topotarget, which had no chemists but was able to run the relevant in vitro assays using both purified HDAC and functional cell-based assays. Today, CROs are integral to the drug discovery process, but 16 years ago it was pretty rare for chemistry contract labs, particularly ones as small as ours, to even be told the biological target let alone be involved in the design process.

HDACs are involved with several biological functions but are perhaps most intimately associated with the cellular process whereby DNA is tightly packaged around classes of proteins called histones. These proteins enable the more than six feet (~2 m) of DNA to pack into the nucleus of every human cell.

When we started work on the project it had already been demonstrated that interference with the process of packing and unpacking of DNA by blocking the function of HDACs had the potential to disrupt aberrant cell replication, and by the late 1990s a small number of HDAC inhibitors had been reported in the scientific literature. We used two of those compounds, a tool compound (a compound with some biological activity but with sub-optimal properties that make it unsuitable for further development) and a natural product with poly-pharmacology (antibiotic as well as anti-proliferative activity). We chose these compounds because they contained structural features that were associated with the known mechanism of action of HDAC inhibition as well as being amenable to drug discovery.

Structural similarities were identified between the compounds and used to generate ideas for hybrid structures. Essentially we took a bit from one molecule and a bit from the other molecule and merged them to come up with a new structure.

Next, we synthesized the compounds that we had designed. Over the next two to three years BioFocus and later another CRO (the Latvian Institute of Organic Synthesis) repeated this iterative design process and synthesized and tested several hundred compounds. From this set of compounds a compound was identified with excellent in vitro potency and efficacy in an in vivo mouse tumor model, a compound that would eventually be called Belinostat. At this point in the process BioFocus' involvement ended and Topotarget continued with the development of this compound.

To cut a long story short, for the next 10 or so years Belinostat was studied in a range of cancer settings with varying degrees of success. Eventually, in 2010 Belinostat was licensed to a company called Spectrum Pharmaceuticals and taken in to clinical development for the treatment of refractory peripheral T-cell lymphoma or (PTCL), a group of rare and usually aggressive lymphomas that develop from mature T-cells and account for about 10-15% of all non-Hodgkins lymphoma (NHL) cases in the US. This trial led to accelerated approval by the US Food and Drug Administration in July.

In 2014, the FDA approved 41 new molecular entities and new therapeutic biological products. Belinostat (Beleodaq) was the 18th—and the first to come out of BioFocus' early discovery work.

Without question, the opportunity to contribute to the discovery of new treatments that prolong and improve quality of life is one of the key motivations and rewards for working in life sciences research. To have been involved in the discovery and development of a drug that is now being used in a clinical setting is something that I am very proud of.

And despite the length of time that it takes to develop a new drug I think that I still recognize the person who started work on the project 16 years ago, minus a few gray hairs!