Personal profile Keeping it simple A discouraging chemistry teacher and a failed rock band just made Harren Jhoti all the more determined to succeed. Sarah Houlton meets the 2008 Chemistry World Entrepreneur of the year

Harren Jhoti gained his love of bass-playing exploits did give him a

ASTEX science at an early age. ‘I remember first taste of entrepreneurship, and, the Eureka moment, when I was at sadly, the rejection that goes with junior school,’ he says. ‘It was a very it. ‘I soon learned not to take knock- sunny day and it struck me what a backs from record companies too beautiful blue colour the sky was. I hard, which made it much easier to asked my teacher why it was blue, deal with being told “no” when I was and she couldn’t answer – it turns raising money to start the business.’ out to be a very complex question.’ The music industry’s loss was Such lifelong curiosity, allied with biochemistry’s gain, and Jhoti’s determination, has led Jhoti to his third year research project piqued current position as founder and chief his interest in science again. ‘I executive of Astex Therapeutics, realised a PhD would mean I could a biotechnology company with a avoid getting a real job for a bit, and new approach to : I spotted an ad in New Scientist for using high-throughput x-ray an MSc at Birkbeck, London, in crystallography to screen small x-ray crystallography of biological molecule ‘fragments’ which are then molecules. It intrigued me – the optimised into drug candidates. thought of seeing something so Jhoti’s scientific interest was small in 3D.’ He hadn’t realised encouraged by his father – Christmas when he signed up that Birkbeck and birthday presents consisted of was then a leading light in structural chemistry sets and microscopes – biology, and that was when he first and a couple of inspirational teachers An Astex researcher School of hard knocks encountered , then at secondary school. But whilst his examines x-ray He decided to study biochemistry head of department, and now head biology teacher was a conventional diffraction data at Queen Mary College in London, of biochemistry at Cambridge – and inspiration, encouraging his UK – the location largely driven by another of Astex’s founders. enthusiasm for science, his his love of music. ‘I formed a band, This led to a PhD with Peter Lindley, chemistry teacher’s influence was Emperor’s Clothes, with some other where he was part of a team that unusual. ‘He told me I shouldn’t take students, and we took a year off to try determined the 3D structure of chemistry as I was really poor at it,’ and make it big,’ he says. ‘Our tutors transferrin, a protein that carries he recalls. ‘Being quite belligerent, expected never to see us again, but iron around in the blood. ‘They’d I figured that was a challenge, and we were realistic and figured that if first grown crystals of it back in took it anyway just to show him he it wasn’t going to happen in a year, 1972,’ he says. ‘My big contribution was wrong.’ then it probably never would.’ His came when I spotted a new approach 54 | Chemistry World | June 2008 www.chemistryworld.org to solving protein structures at a Beckenham, which convinced him much rational design. ‘There was a conference in Australia. Everyone that industry was the life he wanted. sense that intellectual thinking was was sceptical when I suggested leaving drug discovery and, to an it, but we got the software and it Big break extent, that was true – everything opened up a lot of opportunities He secured a job at Glaxo in was being done in a high throughput for determining structures more Greenford in 1991, helping manner, without properly thinking quickly.’ build a structural biology and about what we were doing,’ he From an early period, even at crystallography group to assist in the says. ‘The concept of using small Birkbeck, Jhoti was intrigued by the design of a new generation of drugs. fragments to look at protein binding idea of applying crystallography to ‘It was all new territory,’ he says. was being used elsewhere, but drug design in an industrial setting. ‘And I learnt a lot – the structural applying x-ray crystallography was But there were few industrial jobs biology group at Glaxo became one new.’ going in the late 1980s, so he went to of the best in the industry. But there He faced a tough decision do a postdoc at Oxford with David was still more to be done, and I began – whether to do it within Stuart. ‘I turned down an offer from to be intrigued by the concept of GlaxoWellcome (GW), or leave and the Scripps Institute in San Diego – I applying fragments to drug design.’ set up on his own. ‘We’d just had must have been mad to say no to the This was fundamentally different our second daughter, and the risk sunshine and surfing.’ The project, from what was being done in of not having the money to feed two in the cancer field, was funded by the industry at the time – the vogue was babies was scary,’ he says. But he UK’s Wellcome Trust, and he spent to generate very many compounds, Harren Jhoti accepts his took the leap and went it alone. ‘My a couple of months in their labs in with the ‘numbers’ game overriding award father thought I was tremendously ROYAL SOCIETY OF CHEMISTRY OF SOCIETY ROYAL www.chemistryworld.org Chemistry World | June 2008 | 55 Personal profile

crystallise it, identify fragments

ASTEX that bind, and elaborate them into active compounds that would be interesting leads for development.’ They also started their own drug discovery programme in oncology. ‘This is going really well,’ he says. ‘In the past four years we’ve identified five candidate drugs. Two are now in patients, and we’re seeing interesting early clinical activity. One we’re going alone with, and the other Novartis has an option on. It’s really gratifying when people want to license our compounds – at the start I met many companies, and I might have been speaking Klingon as they had no idea what we were saying. They couldn’t get their heads around why we’d want to start with a compound with only millimolar activity when we need stupid to leave a permanent, secure find proper premises. Jhoti had Astex generates detailed nanomolar compounds as drugs. position, and was astonished that been operating out of a room in structural information But the whole point is that, by using I was setting up my own company. central Cambridge for the first few about potential drug simpler compounds, we can sample The thing that really got him was months, but once the experiments candidates chemical space more efficiently. that I’d have to return my company started working, the hunt for proper We’ve developed high-throughput car.’ labs began. They moved onto the crystallography to do it, and used So he left GW in 1999 and set up Cambridge Science Park, and he it to develop some very interesting Astex Therapeutics, along with his spent the next two or three years leads.’ old mentor Tom Blundell, and Chris recruiting and building the company This year, they’ve added another Abell from the Cambridge chemistry up. ‘I was pleasantly surprised we therapeutic area to the portfolio department. A fourth person, didn’t just attract people from big – antivirals. ‘Our approach lends Roberto Solari – former head of cell pharma who wanted to try working itself to any area as long as there’s biology at Glaxo – had helped Jhoti in a smaller set-up, but some really a protein structure to work shape the business model, and by bright graduates from academia, with. We’ve started a couple of then he was working at investment too,’ he says. programmes, and we’ve already had fund Abingworth, who (along with He also recruited Jose Cosme some interesting results. And I’m Oxford Biosciences) provided the from Scripps in San Diego who particularly proud that three of the initial seed funding for the company had been working on cytochrome 10 most cited papers in the Journal of of about £800 000. P450s all his career. ‘We wanted to Medicinal Chemistry last year were The initial plan was to fund build a fantastic team in this area, from us.’ postdocs at Cambridge to carry out and I managed to persuade him So what’s next for the company? proof-of-concept experiments in to come to us. And that led to our Jhoti says they contemplated fragment screening. ‘The question landmark work on P450s, which was floating on the stock market last was whether, if you took a protein published in and Science – we year, but the climate wasn’t good. crystal and immersed it in a solution were the first people to determine He is now convinced they made the of fragments – small molecules the 3D structures of the human right decision in holding back, as the with a molecular weight of 100–150 isoforms of these enzymes. Jose had share price would have plummeted – you would be able to see any of realised his life’s ambition – and in in the current market turmoil. ‘We’re the fragments binding to it,’ he says. industry rather than academia. I’m going to stay private for a while now,’ ‘Because they’re very small, the very proud of that, and it really put he says. ‘We’ve raised £64 million fragments would have low affinity, us on the scientific landscape.’ in venture financing thus far, and but the ligand efficiency is often Astex now has more than 70 revenues are coming in from our better than for larger molecules. But scientists, and has signed deals collaborations, so we’re in good could we pick up millimolar binding with various pharma companies, shape.’ to the crystal structure? We found including AstraZeneca, Mitsubishi He’s not done badly for someone that you can see it very clearly, and Pharma, Fujisawa (now astellas) and whose chemistry teacher told him crystallography is a very smart way Aventis (now Sanofi-aventis) around ‘My teacher he’d never succeed at the subject. of filtering out non-specific binding the P450 work, and Boehringer- told me I ‘I still don’t really classify myself – if you see electron density for Ingelheim, Schering AG (now as a chemist – more a structural the fragment it can’t be randomly Bayer Schering Pharma), Novartis shouldn’t take biologist,’ he claims. ‘I like to think orientated.’ and AstraZeneca for fragment chemistry as I that this has been an advantage – I drug discovery technology. ‘We can come up with ideas that true Bright minds recruited chemists who learnt how was really poor chemists might think silly, and some These experiments convinced the to expand these fragments into drug at it. I took it of them have actually worked!’ investors, and a larger investment leads using structural biology and round in 2001 brought in £28.4m, iterative medicinal chemistry,’ he to prove him Sarah Houlton is a freelance science which meant they were able to says. ‘We take the protein target, wrong’ journalist based in London, UK 56 | Chemistry World | June 2008 www.chemistryworld.org