Dr John Studley, Science Director at Scientific Update and
Dr Rachel Grainger from Astex Pharmaceuticals got together ahead of our forthcoming Organic Process R&D Conference in Lisbon, Portugal on 23-25 September.
Q: Dr John Studley (JS) Can you give us an overview of Fragment Based Drug Discovery (FBDD) and how you see the technique evolving over the next decade?
A: Dr Rachel Grainger (RG) In FBDD we use low molecular weight compounds (<300Da), which we call fragments, to identify binding pockets on a protein of therapeutic interest. Following hit identification, we grow our fragment hit into a more potent lead compound using a structure-based design approach. During this fragment-to-lead (F2L) phase we rely heavily on X-ray crystallography and computational modelling to design fragment follow-up compounds. Because successful FBDD is dependent on structural information, step changes will come through the way in which we can access high-quality data on systems which were previously intractable to structural elucidation (e.g. using Cryo-EM) and by harnessing the advancements in computational methods to allow us to reliably predict ligand/protein binding affinities. So far FBDD has delivered targeted cancer treatments and the next exciting evolution will be in tackling other disease areas such neurodegenerative disease and CNS disorders.
Q: (JS) What are the challenges of FBDD?
A: (RG) Different FBDD users would have their own opinion on this, but I think chemists would agree that synthesis can be a big challenge which is inherent to the FBDD method. Since the design of a ligand is determined by the interactions it can make with the protein architecture, often we come up with high-quality designs with a strong scientific rationale which we have to de-prioritise because they are really challenging to synthesise by traditional means. At Astex we have started to focus on developing cutting-edge synthetic methodology (such as C-H activation and photoredox) in-house using automated synthesis (such as robotic enabled HTE) to help us to synthesise fragment follow-up compounds in a more time-efficient manner.
Q: (JS) I can see that target affinity and selectivity are the real strengths of this approach- the real challenge is I guess is retaining potency whilst optimising ADME properties. How does this fit with FBDD? Are there generic fragments that can increase solubility for instance?
A: (RG) You’re correct, using the FBDD approach you can achieve high target affinity and selectivity as we can grow our fragment into a lead that is bespoke to our target, however, there often isn’t a big trade off in potency whilst optimising ADME properties. During F2L we tend to get a deep understanding of SAR around the fragment core by documenting how incremental changes affect potency. So, providing we preserve the key ligand/protein interactions we can tailor the ADME properties in a ligand efficient manner.
Q: (JS) When does a fragment become a lead?
A: (RG) Well this is difficult to answer precisely and will be project dependent, but you could say that a fragment becomes a lead when the optimisation of potency is no longer the primary objective and the focus now is on improving PK/PD properties and improving target specificity.
Q: (JS) There are currently 2 approved drugs discovered using FBDD (Venetoclax and Vemurafenib)-would you expect to see more now the technique is well established and how does this compare to other lead identification approaches?
A: (RG) Well there are now 3 approved drugs discovered using FBDD, the third being Balversa (erdafitinib) which was granted accelerated approval earlier this year for metastatic bladder cancer and is derived from a collaboration between Astex & Janssen subsequent to a collaboration between Astex & Newcastle University. According to a recent post on Dan Erlanson’s ‘Practical Fragments’ blog (06.10.18) there are currently ~40 fragment-based molecules in various stages of clinical trials: Phase I (18), Phase II (14), Phase III (4 + erdafitinib) so it seems to be a widely practised technique now. Of course, there’s no ‘one shoe fits all’ approach, but FBDD has shown success against targets that were not druggable by other techniques and I imagine we will see many more prospective candidates before long.
Q: (JS) Do fragments ever stabilize high energy protein conformations giving false positives? Do you always get good translation of activity to the in vivo setting?
A: (RG) Good question, sometimes when a fragment binds it can induce a conformational change causing part of the protein to move but we always use orthogonal assays such as (Tm, ITC, SPR, NMR etc) to corroborate ligand-binding affinity and rule out false positives. Using the fragment-based approach we often get multiple leads series emerging for the same target and we can then prioritise these based on in vivo activity.
Q: (JS) I enjoyed reading your recent article in Chemical Science (2019, 10, 2264) on the use of photoredox chemistry to functionalize key positions and build out fragment vectors. Are you looking at other late stage functionalization methodology?
A: (RG) Thank you, yes, we’re currently working on two other photoredox-mediated late stage C–H functionalisation methods which we hope will be in print towards the end of the year, but as you will appreciate, unfortunately I can’t give any specifics about the reactions at this time.
Q: (JS) Can you tell me a little about your role at Astex Pharmaceuticals?
A: (RG) My role at Astex is a Sustaining Innovation (SI) Postdoctoral Researcher in the Medicinal Chemistry department. My work focuses on the use of automated synthesis to develop state-of-the-art synthetic methods (e.g. transition metal catalysed C–H activation and photoredox catalysis) for functionalisation of fragments and medicinally relevant heterocycles. During my postdoc I have established a nanogram-to-gram workflow for reaction optimisation, used this to develop new photoredox mediated methods relevant to FBDD and now I am starting to train medicinal chemists at Astex to use this platform for creative problem solving on live projects.
Q: (JS) Who inspired you to study chemistry?
A: (RG) My parents always gave me STEM gifts as a kid, probably to keep me occupied and to stop my incessant questioning about everything. It’s funny because my passions at school were actually Maths and Art but my sixth form Physics teacher Roy Allen encouraged me to pursue a career in Science as he realised I had an aptitude for it, without his encouragement I’m sure I would be a failed artist. I chose Chemistry as I liked the practical aspects of the subject but also how it employs creative problem solving; I love the fact that you can have an idea, get in the lab and test it, and quickly get an answer.
