Harren Jhoti, Ph.D.,
CEO, Astex Therapeutics, Cambridge, UK.
In the 1980s, the potential of X-ray crystallography to provide structural information to aid drug design was just emerging. For Harren Jhoti, understanding and applying this ability of biophysical techniques to 'visualize' small entities such as proteins attracted him to study protein crystallography in his M.Sc. and Ph.D. at Birkbeck College, University of London, UK. "The other aspect of protein crystallography that appeals to me is its true multidisciplinary nature — you can experience molecular biology, biochemistry, enzymology, physics and computational analysis during the process," says Jhoti.
Following a postdoc at the University of Oxford, UK, in 1991, he joined Glaxo, the largest pharma company in the world at the time. "My job was to help build a protein crystallography facility that could be used to help rationally design drug molecules — this was really fulfilling an early ambition to get into structure-based drug design," says Jhoti. He spent 9 years with the company helping to build one of the largest structural biology groups in industry, and became Head of Structural Biology and Bioinformatics.
"However, during the late 1990s, I began to get interested in a new approach to drug discovery — that of fragment screening and in particular how structural biology could be used in it," recalls Jhoti. In this strategy, compounds considerably smaller than those used in conventional high-throughput screening are identified and optimized using biophysical approaches such as X-ray crystallography. So, in 1999, Jhoti resigned from GlaxoWellcome to found a fragment-based drug discovery company called Astex, together with Sir Tom Blundell (in whose department at Birkbeck he had initially studied) and Chris Abell, both from Cambridge University, UK.
Jhoti started as Chief Scientific Officer, leading the development of the company's high-throughput X-ray crystallography platform and its application in fragment-based drug discovery. In the past 8 years, Astex has established itself as one of the leaders in the field, raising over UK£70 million and signing collaborations with companies such as Johnson & Johnson, Novartis and AstraZeneca. "The biggest thrill is when one of our drug candidates enters clinical trials — we now have three drugs all discovered internally that are being tested in patients with cancer," says Jhoti.
Now, as the CEO, Jhoti, together with other senior managers, is responsible for the company's R&D focus and ensuring sufficient funds are available to continue to discover and develop their drug candidates. "As well as trying to stay close to the science, I spend a lot of time interacting with our investors and executives from other companies in the pharma/biotech sector," he says. For those also seeking to establish a biotech company, he strongly emphasizes the need to be able to sell a vision and to build a good network of people. "Also, don't hesitate to take a risk if you really believe in your idea," says Jhoti. "It would have been very easy for me to have stayed at Glaxo — but I believed fragment discovery would work so I took the risk and jumped, and have never looked back!"
Keith Wilson, Ph.D.,
President and CSO, Takeda San Diego, California, USA.
An introduction to X-ray diffraction during an undergraduate physics course was the spark for Keith Wilson's decision to pursue a career in structural biology. "I loved physics, but I didn't fancy a life immersed in quarks, and X-ray crystallography opened a window for me into the universe of protein structures," says Wilson. "I was intrigued with the idea of studying the machinery of life inside cells, and so I chose a Ph.D. in biophysics at the University of Oregon, examining how proteins worked on the atomic scale".
Following his Ph.D., Wilson was keen to apply the techniques of X-ray crystallography to drug design, and in 1992 he joined Vertex Pharmaceuticals, Boston, USA, an emerging biotech among those companies pioneering structure-based drug discovery at the time. He spent 10 years there working on multiple drug discovery programmes, including one that led to the hepatitis C virus protease inhibitor, telaprevir, which is now in Phase III trials. In addition, he gained skills in contracts and alliance management while serving as a co-project leader for a major collaboration between Vertex and Novartis on kinase inhibitors.
These abilities proved valuable following his next career move in 2002 to Syrrx, another start-up biotech company focusing on structure-based drug design. There, as Vice President of Structural Biology, he played a substantial role in the transition of the company from one based on its platform technology — high-throughput X-ray crystallography — to one with a product pipeline. "It was clear upon joining Syrrx that we would have to make significant scientific and business direction changes to survive as a company, and my previous experiences had prepared me well for those jobs," says Wilson. While continuing with his responsibilities in structural biology, he was promoted to Vice President of Business Development in 2003 and established and managed partnerships with companies including Roche and Biogen-Idec.
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Syrrx was subsequently acquired by Takeda in 2005 to gain access to its people, platform technology and internally discovered drug candidates, including the dipeptidyl peptidase 4 inhibitor alogliptin, which has been submitted for regulatory approval to treat diabetes. In 2007, Wilson became President and Chief Scientific Officer of Takeda San Diego, which focuses on designing drug candidates for metabolic diseases and cancer, and supports Takeda's structural biology needs worldwide.
Looking back over his career so far, Wilson believes his initial training in physical sciences had a key function beyond its direct application. "All that math trained me how to think, to reason, and to pay attention to details, and if you can do those three things well, you can do just about anything you want," he says. "I was also never afraid to take a risk on new challenges and experiences, which is how I learned business development, negotiations, and acquisitions in addition to the science."
