THE SGC STORY – AN INTERVIEW WITH CHAS BOUNTRA

Chas is a Professor of Translational Medicine in the Nuffield Department of Clinical Medicine and Associate Member of the Department of Pharmacology at the University of Oxford. He is also a Visiting Professor in Neuroscience and Mental Health at Imperial College, London. Chas is an invited expert on several government and charitable research funding bodies, and an advisor for many academic, biotech and pharma drug discovery programmes. He was voted ‘one of the top innovators in the industry’ in 2012. Previously, Chas was Vice President and Head of Biology at GlaxoSmithKline. He was involved in the identification of more than 40 clinical candidates for many gastro-intestinal, inflammatory and neuro-psychiatric diseases.

Support for open innovation in research is increasing across technology sectors around the world. In June 2014 Tesla boldly released their patents on electric vehicle technology to accelerate its development. Research companies, both large and small, can waste resources and time when investigating the same targets behind closed doors and patents, when talking to each other would better target their focus elsewhere to quicken advancements and avoid repeat failure.

One institution shaking things up in the pharmaceutical industry and doing things a bit differently is the Structural Genomics Consortium (SGC) in Oxford.

The SGC is a dedicated example of the open innovation model, as their stated mission is to focus on less well explored areas of the human genome and share their results freely and openly with the scientific community and collaborators. This approach has already led to the sharing of over 1200 new protein structures online and the development of over 30 high quality small molecule chemical probes being made available for epigenetic proteins.

The story of the SGC began 10 years ago, when it was established to produce openly accessible academic research to support the drug discovery process. A process that, a decade later, SGC Chief Scientist Professor Chas Bountra reflects on:

“We [the industry] don’t know how to do target discovery, we still don’t understand human disease well enough”.

A surprising statement in the face of the overwhelming success that the SGC has seen, yet it bears a serious point when one considers that despite the sequencing of the human genome, no revolutionary advance in drug discovery has come; we are still searching for ‘cures’ for cancer, diabetes, chronic inflammatory conditions and a multitude of others. Nonetheless the progress made towards these laudable goals has been considerable, and the SGC has played a major role in advancing the burgeoning field of epigenetics.

The SGC’s small molecule probe project targeting epigenetic proteins was initiated in 2008, initially just with financial support and expertise from GSK, now with nine other pharmaceutical companies and the Wellcome Trust, to the combined tune of over £135m in funding together signalling a “paradigm shift in the industry” according to Professor Bountra. Put simply, the project aimed to provide tools to interrogate biology where before there were none. Professor Bountra continues: “A useful chemical probe must be potent, selective and cell active”. That is to say research with ‘dirty’ (off-target effecting) and in-vitro only activity probes is not acceptable in the face of exquisitely complex systems which we must go after, such as the CNS for Alzheimer’s. In delivering probes meeting these criteria for under-researched targets, including target verification through use of different chemotype probes and inactive control testing, the SGC serves as a bridge between the worlds of academia and industry. This bridge is vital to rebuild confidence between the two when, Professor Bountra tells us,

“Industry feels that up to 50% of the academic literature is not reproducible when they come to test it”

creating an unsustainably low level of trust that can only be repaired through closer collaboration.

Global and local collaborations form a key part of the SGC’s strategy, one of which has borne a game changing small molecule for targeting cancer. The story of JQ1 is an excellent example of what open innovation between scientists across disciplines in the clinic and the lab can achieve, and in a space of time that no other approach could. Jay Bradner’s research group at Dana-Farber worked with the SGC to publish on the inhibition of BET bromodomains, which on discovery of their importance to the function of oncogenic MYC protein, led to a resurgence in interest targeting this previously elusive functionality. In particular, a candidate drug spawned from this research, OTX-015, being developed by OncoEthix in phase 1 trials led to a buyout from Merck in late 2014 for $375 million. The valuable promise shown by this class of inhibitors against cancer has led to other pharmaceutical companies beginning research on them, and in the ensuing 4 and a half years Professor Bountra informs us there have been 6 new companies established, with 6 new molecules and 12 clinical studies and hundreds of academic publications across the globe – a huge achievement. Moreover, these quality probes are enabling precise interrogation of their target proteins to discover new biology, particularly relating to inflammation. Even deciding which assays to perform to find this new biology is itself a huge challenge.

Professor Bountra also says that the “interest from patients has never been higher”, to the extent that they and their relatives have been in his office offering their tissue for study, and setting up foundations – an extraordinary show of support and source of motivation for the science. Much of this remarkable story has stemmed from the 2010 Nature publication of the BET target validation and the decision to share JQ1 openly as a tool for research. It is fantastic progress in just five years of research and this ‘crowdsourced science’ looks set to continue producing more exciting results.

Panacea Innovation’s Biostars competition provides a superb opportunity for applicants to exploit this way of doing science, by either: developing their own ideas, or utilising scientific output and mentorship from the SGC in order to turn science into commercial reality.

 

Written by Oliver Coleman, Editor-in-Chief