Abstract
Ashok Venkitaraman, MD, PhD, professor of cancer research at the University of Cambridge in the UK, and director of the Medical Research Council's Cancer Cell Unit in Cambridge, discusses research to systematically extend the repertoire of druggable targets in cancer.
An academic project aims to systematically broaden the range of targets for small-molecule drugs
“Of the universe of potential drug targets, probably less than 10% are routinely accessible to existing methods for small molecule discovery,” says Ashok Venkitaraman, MD, PhD, professor of cancer research at the University of Cambridge in the UK, and director of the Medical Research Council's Cancer Cell Unit in Cambridge. “So how does one extend the repertoire of targets to include some of the undrugged and so-called undruggable classes?”
That's one of the challenges taken on by the Cambridge Molecular Therapeutics Program, which Venkitaraman coordinates and discussed with Cancer Discovery's Eric Bender
How is the program structured?
We formulated a collaborative approach involving people in disciplines ranging from physics, synthetic organic chemistry, structural biology, and cell biology to clinical research, all working together in project teams. The challenge has been to find like-minded investigators willing to sublimate some of their personal scientific aspirations into a collective effort. However, we find it's actually possible in academia and can bring fantastic results beyond the reach of any individual lab.
How do you expand the range of druggable targets?
We're exploring the idea that macromolecular complexes between proteins, and between proteins and other molecules, are not only fundamental to the regulation of disease-altered pathways, but may offer more attractive selective targets for modulation by small-molecule drugs. This has not attracted much systematic effort in the pharmaceutical industry, let alone in academia.
Why not?
There are many well-recognized scientific challenges in drugging macromolecular interactions. Among them, the buried surface areas when big molecules come together may be very large, making it hard to identify those regions of the interface which contribute most to the binding free energy. Another is that when macromolecules come together to form complexes, adaptive structural changes may make it difficult to access their components.
How has your group picked specific targets?
We have gone after clinically validated targets as well as structural classes of potentially attractive targets that have not previously been drugged. In the first category, for example, where kinase inhibitors have been developed but are not optimal in patients, we are asking if we can regulate those enzymes not by targeting the ATP site but rather through regulatory interactions such as allosteric mechanisms. In the second category, we have taken examples for which there is clear evidence in the literature to suggest that they represent an important class of potential targets that have simply not been drugged before.
What are your platforms for discovering potential agents?
We've been exploring two broad approaches.
The first one has used methods pioneered by my close colleagues and collaborators Christopher Abell, PhD, who is an organic chemist, and Tom Blundell, DPhil, who is a structural biologist. We use very small chemical moieties, fragments, rather than large drug-like molecules, to explore the shape of interfaces where macromolecules come together. Using iterative structure determination of where these fragments bind to such an interface, you can guide the synthetic organic chemistry such that you explore the surface features and develop more and more potent and larger molecules from very small fragments. The process is driven by iterative rounds of binding, crystallization, and synthesis.
Targeting macromolecular complexes with small-molecule drugs “has not attracted much systematic effort in the pharmaceutical industry, let alone in academia,” says Ashok Venkitaraman, MD, PhD.
Targeting macromolecular complexes with small-molecule drugs “has not attracted much systematic effort in the pharmaceutical industry, let alone in academia,” says Ashok Venkitaraman, MD, PhD.
The second platform, developed in my own laboratory, uses custom-designed libraries of larger and more complex compounds, whose physico-chemical and structural characteristics, we believe, make them more likely to bind to the classes of targets we are attempting to drug. Again, we use structure determination to guide chemical synthesis.
How do those 2 platforms work together?
We've been using them in parallel, and we're beginning to glimpse more general rules about which approach may be more applicable to specific target classes.
In some instances we are not able to get initial hits using the fragment-based approach, whereas the library-based approach has provided the initial starting traction. We don't fully understand why yet, and there are many possible explanations. For instance, with higher-affinity, larger compounds, you can develop assays that directly measure their ability to compete at a macromolecular interface, whereas fragments generally have a low binding affinity and must be screened against unliganded targets. The latter approach may not work so well when adaptive structural changes accompany macromolecular complex formation. Conversely, there are other instances where the fragment-based approach has been highly successful.
What progress have you made so far?
We have gone from characterization of challenging and previously undrugged targets to developing potent inhibitors that induce selective cellular effects consistent with target engagement. We hope that in the next 2 to 3 years, some projects will reach a point where we can consider moving towards clinical applications with companies.
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