Good chemistry: a South African rising star

30 Nov 2009

Patrick Adams

Source: TropIKA.net

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Professor Kelly Chibale.

In the sleek laboratories of the University of Cape Town (UCT), the future of African drug discovery is being written. Professor Kelly Chibale is one of its lead authors.

As UCT Chair of Drug Discovery, Chibale oversees projects devoted to novel therapies for HIV, TB, malaria, cardiovascular disease and hypertension at one of the few centres of medicinal chemistry on the continent. Africa lacks capacity in many areas of research, but there may be no shortage as striking as its dearth of drug discovery. For South Africa, filling that gap is priority number one, and Chibale is leading the way.

“There are basically three broad areas of malaria that I’m working on,” he says. “One is a hit-to-lead programme in collaboration with the Medicines for Malaria Venture (MMV). It’s quite a big programme. Basically, MMV paid for high-throughput screening (HTS) of a 35,000 compound library, and we initially prioritized more than 200 hits from that screening.”

A native of Zambia, Chibale arrived in South Africa in 1996 after a two-year fellowship at the Scripps Institute, San Diego, USA. At the time, he says, the research paradigm was to isolate compounds from a plant, determine the chemical structure, and, if it was new, publish the results. “There was no regard for the intellectual property and meaningful integration into modern drug discovery paradigms,” he says. “As a result, nothing of substance could be patented.”

Changing the culture

Over the past decade, Chibale has worked to change that culture, mainly through collaborations with pharmaceutical firms, non-profit groups and international organizations. In 2005, his UCT lab was selected as a “centre of excellence” by WHO/TDR, becoming a member of TDR’s Medicinal Chemistry, Screening, Drug Metabolism and Pharmacokinetics Network. The network, one of four devoted to different parts of the drug discovery chain, links African institutions like UCT with industry partners, providing Chibale and his two-dozen postdocs access to tools such as high-throughput screening (HTS) not found in South Africa.

Around the same time, Chibale received a grant from MMV to pursue hit-to-lead medicinal chemistry integrating absorption, distribution, metabolism, and excretion (ADME) characteristics of promising compounds. “We profile the compounds extensively, and then we show that they are orally bio-available. Doing the ADME is critical because you need to have a sense of the compound’s solubility, permeability, and metabolic stability, all of which have a direct bearing on its oral bioavailability, efficacy and toxicity.”

Progress has been good, he says. “We’ve actually delivered several leads. We can’t work on everything at once, so we’ve prioritised three that are all from different families, and we have back-ups for them, which is great. So we’ve gone forward with those three –teased out information, understood the ADME profile, and demonstrated efficacy and safety in animal models. The data are looking very exciting.”

No less exciting, he says, are the capacity-building fruits of collaboration. “MMV basically pays a consultant from the pharmaceutical industry to mentor me and my postdocs, and I’ve had a similar arrangement with WHO/TDR. We’re getting the kind of exposure most people only dream about. And I’m learning. We get input from people with a lot of experience taking drugs to the market, people who understand the issues that you’re dealing with. So we’re benefiting enormously from that.”

Patience and resolve

Medicinal chemistry is extremely challenging, says Chibale, not least for its unpredictability. Rarely is the best strategy an obvious choice. It takes patience and resolve, to say nothing of time and resources. Current estimates for the cost of taking a compound from the laboratory to the marketplace are between $800 million and $1 billion dollars. And while the reasons for that price tag vary – from rigorous clinical trials to the layers and layers of regulatory hurdles along the way – a clear contributor is the sheer length of time: on average 12 to15 years for a novel molecular entity (NME).

One effect of this, says Chibale, has been a reticence on the part industry veterans to take on R&D for various classes of drugs with a problematic past, despite what may be a promising therapeutic potential. “There’s a perception out there that some compounds, such as irreversible inhibitors, drugs that covalently modify the enzyme, are high-risk in terms of their potential for toxicity,” he says. “People with 30 years of experience will say ‘Oh, that’ll never work. There are going to be problems with that. Don’t try it.’ But we have plenty of drugs that are irreversible inhibitors, and toxicity never stopped their development. Penicillin is one.”

Perceptions can be dangerous, he says. “I’m not saying one should disregard advice. But if there’s a problem with the molecule by virtue of the presence of a structural moiety known to be associated with toxicity and other shortcomings– we call it a ‘structural alert’ – the priority at that point should be to find the solution, to confirm or disprove. Data, data, data. That has always guided my work.”

Taking the lead

In addition to leveraging expertise, Chibale has been able to use those partnerships in domestic funding. Cape Biotech, one of South Africa’s semi-governmental Biotechnology Regional Innovation Centres (BRICs), recently awarded Chibale funding for a new drug discovery centre set to open in the heart of Cape Town next year.

“Cape Biotech is investing in drug metabolism and pharmacokinetics (DMPK) and parallel synthesis and purification platforms, which are critical to the projects I’ve been doing with MMV.” The mission of the new centre is to serve as an incubator for promising start-up companies spun out of the research. MMV is currently supporting a staff of six researchers in Chibale’s lab, and that number is expected to increase significantly if progress and infrastructure expansion is satisfactory.

“We plan to hire top people from pharma to head up medicinal chemistry, DMPK, and biology within the drug discovery centre,” he says, because for now anyway, South Africa can’t do it alone. “We have to import expertise and get these people to work with South African people and transfer their skills.” He hopes by demonstrating that “science can pay” South Africa can attract young scientists to the field. “We’re losing talent to other disciplines. But I think that, if we can strengthen the perception of scientists as entrepreneurs, it could resonate very well with young researchers.”

Chibale keeps a quote close at hand, something a pastor said years back: “Three percent of the population makes things happen. Five percent watches things happen. And the rest wonder what happened.”

“I love that line because it really speaks to self-empowerment,” he says. “We have to ask ourselves ‘What are we doing to change our situation?’ It’s not enough to just blame politicians. We have to take the lead in solving our own problems, and there have to be real success stories to inspire that.”

About Kelly Chibale

Born: March 31, 1964, in Luanshya, Zambia. Grew up in Kitwe, Zambia.

Education: University of Zambia, BScEd (chemistry with distinction) 1983-87; University of Cambridge (UK), Cambridge Livingstone Trust Scholar and PhD student (research with Stuart Warren), 1989-92.

Family: Married (September 8, 1990) to Bertha with three sons: Kalaba (born, March 14, 1992, Cambridge, UK), Suwilanji (born, August 23, 1994, Liverpool, UK), Sechelanji (born, July 5, 2002, Cape Town, South Africa).

Interests: Christian meetings, boxing, soccer, gym, jogging, half marathons.

Career

Sir William Ramsay British Postdoctoral Research Fellow, Department of Chemistry, University of Liverpool, UK, (research with Nick Greeves), 1992-94.
Wellcome Trust International Prize Travelling Research Fellow, Scripps Research Institute, USA (research with K C Nicolaou), 1994-96.
Sandler Sabbatical Fellow, University of California San Francisco, USA (with Jim McKerrow), 2002.
Invited Professor, Université des Sciences et Technologies de Lille, France (with Jacques Brocard), 2002.
Full Professor (ad hominem promotion), Department of Chemistry, UCT, 2007.
Tier 1 South African National Research Chair in Drug Discovery under the South African Research Chairs Initiative, 2008.
US Fulbright Senior Research Scholar, University of Pennsylvania School of Medicine, USA (with Doron Greenbaum), 2008.
Visiting Professor, Pfizer Global R & D (Sandwich, UK), 2008.
Director, South African Medical Research Council Drug Discovery and Development Research Unit, 2009.
Founder and Scientific Director, Holos 3ple-D Drug Discovery, 2010