Career snapshots In the past decade, high-throughput structure determination with X-ray has demonstrated its value as a tool not just for optimizing lead compounds, but also for lead discovery. This month, we feature two leaders in the application of X-ray crystallography in .

crystallography facility that could be used to drug discovery. In the past 8 years, Astex has , Ph.D., CEO, help rationally design drug molecules — this established itself as one of the leaders in the Astex Therapeutics, was really fulfilling an early ambition to get into field, raising over UK£70 million and signing Cambridge, UK. structure-based ,” says Jhoti. collaborations with companies such as He spent 9 years with the company helping Johnson & Johnson, Novartis and AstraZeneca. to build one of the largest structural biology “The biggest thrill is when one of our drug groups in industry, and became Head of candidates enters clinical trials — we now have Structural Biology and . three drugs all discovered internally that are In the 1980s, the potential of X-ray “However, during the late 1990s, I began to get being tested in patients with ,” says Jhoti. crystallography to provide structural information interested in a new approach to drug discovery Now, as the CEO, Jhoti, together with to aid drug design was just emerging. For Harren — that of fragment screening and in particular other senior managers, is responsible for the Jhoti, understanding and applying this ability how structural biology could be used in it,” recalls company’s R&D focus and ensuring sufficient of biophysical techniques to ‘visualize’ small Jhoti. In this strategy, compounds considerably funds are available to continue to discover entities such as attracted him to study smaller than those used in conventional and develop their drug candidates. “As well crystallography in his M.Sc. and Ph.D. high-throughput screening are identified and as trying to stay close to the science, I spend a at Birkbeck College, , UK. optimized using biophysical approaches such as lot of time interacting with our investors and “The other aspect of protein crystallography X-ray crystallography. So, in 1999, Jhoti resigned executives from other companies in the pharma/ that appeals to me is its true multidisciplinary from GlaxoWellcome to found a fragment-based biotech sector,” he says. For those also seeking — you can experience molecular drug discovery company called Astex, together to establish a biotech company, he strongly biology, , enzymology, physics with Sir (in whose department at emphasizes the need to be able to sell a vision and and computational analysis during the Birkbeck he had initially studied) and , to build a good network of people. “Also, don’t process,” says Jhoti. both from Cambridge University, UK. hesitate to take a risk if you really believe in your Following a postdoc at the University of Jhoti started as Chief Scientific Officer, idea,” says Jhoti. “It would have been very easy Oxford, UK, in 1991, he joined Glaxo, the leading the development of the company’s for me to have stayed at Glaxo — but I believed largest pharma company in the world at the high-throughput X-ray crystallography fragment discovery would work so I took the risk time. “My job was to help build a protein platform and its application in fragment-based and jumped, and have never looked back!”

drug discovery programmes, including one Syrrx was subsequently acquired by Takeda Keith Wilson, Ph.D., that led to the hepatitis C virus in 2005 to gain access to its people, platform President and CSO, inhibitor, telaprevir, which is now in Phase III technology and internally discovered drug Takeda San Diego, trials. In addition, he gained skills in contracts candidates, including the dipeptidyl peptidase 4 California, USA. and alliance management while serving as a inhibitor alogliptin, which has been submitted for co-project leader for a major collaboration regulatory approval to treat diabetes. In 2007, between Vertex and Novartis on kinase Wilson became President and Chief Scientific inhibitors. Officer of Takeda San Diego, which focuses An introduction to X-ray diffraction during an These abilities proved valuable following on designing drug candidates for metabolic undergraduate physics course was the spark his next career move in 2002 to Syrrx, diseases and cancer, and supports Takeda’s for Keith Wilson’s decision to pursue a career another start-up biotech company focusing structural biology needs worldwide. in structural biology. “I loved physics, but I on structure-based drug design. There, as Vice Looking back over his career so far, Wilson didn’t fancy a life immersed in quarks, and X-ray President of Structural Biology, he played a believes his initial training in physical sciences crystallography opened a window for me into substantial role in the transition of the company had a key function beyond its direct application. the universe of protein structures,” says Wilson. from one based on its platform technology — “All that math trained me how to think, to “I was intrigued with the idea of studying the high-throughput X-ray crystallography — to reason, and to pay attention to details, and if machinery of life inside cells, and so I chose a one with a product pipeline. “It was clear you can do those three things well, you can do Ph.D. in biophysics at the University of Oregon, upon joining Syrrx that we would have to make just about anything you want,” he says. “I was examining how proteins worked on the atomic significant scientific and business direction also never afraid to take a risk on new challenges scale”. changes to survive as a company, and my and experiences, which is how I learned business Following his Ph.D., Wilson was keen to previous experiences had prepared me well development, negotiations, and acquisitions in apply the techniques of X-ray crystallography for those jobs,” says Wilson. While continuing addition to the science.” to drug design, and in 1992 he joined Vertex with his responsibilities in structural biology, Pharmaceuticals, Boston, USA, an emerging he was promoted to Vice President of Business biotech among those companies pioneering Development in 2003 and established and web site managed partnerships with companies including Career snapshots: http://www.nature.com/naturejobs/ structure-based drug discovery at the time. magazine/career_snaps.html He spent 10 years there working on multiple Roche and Biogen-Idec.

nature reviews | drug discovery volume 7 | september 2008 | 783