Introduction to the modern and changing role of the medicinal chemist

The pharmaceutical industry has changed dramatically over the past years and with it the role of the Medicinal Chemist. The traditional “under one roof” approach to drug discovery has been replaced by the outsourcing of compound synthesis and biological screening to vendors worldwide in an effort to reduce costs, with the recent annual R&D expenditure across nine large companies being estimated to be a staggering $60 billion, yet per year this investment has resulted in the approval of only 7 NMEs in total on average.¹

Numerous expensive Phase II failures have brought into ever sharper focus the need to pick the right, disease-relevant, targets. Indeed, a re-emphasis on assessing which targets/pathways deliver clinical efficacy has spurred numerous scientific advances from the Medicinal chemistry community. The traditional remit of the Medicinal Chemist solely delivering small drug-like molecules that are active against a target preselected by a Biologist is changing. Chemical biology and chemical genetics are coming to the fore as examples of Medicinal Chemistry more proactively engaging in the exploratory stage of target validation. Recent advances in structural biology, computational chemistry and bioinformatics have also enabled advances in areas such as the design of safer molecules.

The diversity of compounds that medicinal chemists deliver is changing too. Target space is not always “rule-of-5 compatible” and a recent focus on the delivery of ligands that modulate a greater array of targets has fuelled an expansion of the chemical tool-box to include aptamers, chemically stabilized proteins, oligonucleotides, carbohydrates and macrocycles to name but a few. The desire to further deliver drugs in biologics space will almost certainly continue to drive innovation in “Beyond Rule of 5” chemical space.

Finally, the days when all of the science related to drug discovery was conducted behind closed doors are over. More than ever Pharma companies are partnering with external organizations (both academic and other Pharma/Biotech) to share knowledge and tap into specific expertise and technology lacking within in their portfolios. Working in these consortia, pre-competitive or otherwise, provides an additional avenue of opportunity for Medicinal Chemistry to exert a greater influence on scientific agenda.

Recent advances and impact from chemical biology and structural biology

In the past decade there have been numerous scientific advances in the fields of computational science, protein crystallisation, structural biology and biophysics, particularly in the arena of membrane associated targets, driven by close association of Pharma and academia. This is now making binding site analysis and structure based drug design (SBDD) a realistic future goal across a wider range of target classes. With a more accurate assessment of binding site morphologies these advances could further broaden our concept of druggable target space. Parallels can conceivably be drawn with the field of kinases, which have transitioned from being regarded as largely undruggable to being relatively attractive targets in the space of a decade, largely educated by SBDD. Pharma companies and academic-industrial collaborations have already begun to harness the structural breakthroughs of the last 5-years on g-glycoprotein coupled receptors (GPCRs) to not only access proteins X-ray, but to also generate protein-ligand co-crystals to guide the medicinal chemists as to binding site, binding mode and ultimately towards a better understanding of the protein dynamics of GPCR coupling.²

However, many therapeutically attractive protein targets and complexes remain beyond small molecule drug space. In fact, of the ~30,000 human genes identified it has been estimated that only around 10% of these encode proteins that are anticipated to be applicable for modulation using classical small molecule drugs.³ Accordingly, there has been increased attention on how we might disrupt these and the estimated 130k-650k distinct protein-protein interactions (PPIs) in the human body.⁴ Currently this area still presents a major challenge to medicinal chemistry, having traditionally been the domain of natural products, peptides, toxins and antibodies. As a result, there has been increased momentum to harness understanding of these molecular classes into a designing a greater diversity of smaller-molecule drug-like products.⁵ Medicinal chemistry has seen clear progress in this area in recent years via small molecules that leverage small molecule binding sites that either overlap with or allosterically disrupt PPIs, with examples including BRD4, LEDGF/p75 inhibitors.¹ An alternative approach has been to design scaffolds that mimic protein secondary structural elements but retain drug-like properties, including ß-turn mimetics, ß-helix mimetics such as stapled peptides, and macrocycles influenced by natural products. Furthermore, new phage display methods have also been developed to express very large arrays of novel small peptides and oligonucleotides based around an approximate design template, thereby permitting rapid optimisation via phage display panning.⁶

Despite these ongoing improvements in the chemistry repertoire for more effectively tackling difficult targets, there is increased shared responsibility for medicinal chemists and biologists to work together to ensure that the correct targets are selected in the first instance, prior to initiating the full drug delivery process. Although there has been a drive to harness the advances in genetic and proteomic profiling of individuals who exhibit therapeutically relevant phenotypes, this approach is only likely to provide target evidence in a limited number of cases that proves compelling enough on its own to warrant a full program (eg CCR5 or NaV1.7). As a result, there is clearly a need to develop and apply other methods for target identification and validation. Traditionally this gap was bridged by chemistry delivering a small molecule tool to biologists to generate in vitro or in vivo rationale in preclinical species, operating in isolation. However, this approach can prove unsuccessful owing to either an incomplete understanding of a relatively poorly characterised tool or poorly understood relevance of many preclinical disease models. In response, medicinal chemists have started to make a much broader contribution to biology studies at the chemical biology interface, harnessing a variety of techniques to answer important biology questions. These include the application of chemogenomic compounds sets to deconvolute disease relevant phenotypic screening data and the application of chemical-based proteomics methods such as activity-based proteomic profiling (ABPP) or affinity based techniques to elucidate proteins and signalling pathways in cell lysates or in a whole cell environment.7 Increasingly these are being used in conjunction with state-of-the-art quantitative mass spectrometry to enable the identification of members of multi-protein complexes, further enabling an understanding of the distinct protein complexes associated with diseased relative to healthy cells. This offers the opportunity to gain clarity around the behaviour of the initial target but to also potentially identify new targets relevant to the disease. Beyond the target identification, other chemical biology methods such as molecular imaging tools can be generated to highlight the location and expression levels of the target within specific tissues, further educating the program as to the necessary target compound profile. Furthermore, the tools from this phase of the exploratory decision-making process can also sometimes be reused or adapted to enable the drug discovery process in other ways such as markers of drug distribution or the development of preclinical occupancy biomarkers of target engagement.

Changes to the industry-academia interface

The majority of breakthroughs in target biology research have occurred in the academic environment and this has driven a change in the way that industry and academia have operated over recent years.  However, the days of drug discovery companies providing significant funding to areas of research outside of their scientific focus have largely passed.  Commensurate with this, there is increased incentive for genuine collaboration between academia and industry to find common scientific ground and work together to find solutions that benefit both parties.   Through such partnerships a broader array of research can be explored than if companies and academia work in isolation with co-proposals for external funding as well as in-kind sharing of ideas, infrastructure and materials becoming more commonplace. Although this in theory sounds, and is, a sensible goal, it is one that will likely to take time to fully deliver and will not be without pitfalls.  The union of two historically quite different scientific groups driven by different goals and ideals will likely take time and require effort from both parties to build an open and trusting relationship.  It will also be critical to identify and openly communicate areas of scientific need such that pre-competitive opportunities can be found and the results openly shared and published.

So where does MedChem fit into all of this?  Well, in addition to requiring new compounds and technologies to tackle Protein-Protein interactions (PPIs) and other difficult targets, there is also an increased need to provide state-of-the-art tools to aid target identification and probe protein structure and function. Generally this work is early enough to be precompetitive making it an ideal area for collaboration with academia and consortia.

To date, a number of network groups have been established with the aim of fostering communication and driving innovative solutions to scientific problems facing the drug discovery industry.  One such collaboration between academia and over 20 organizations has received joint investment from several research councils (EPSRC, BBSRC and MRC) to aid research and knowledge-sharing at the chemical biology interface.  The drive of Pharma companies to become part of a fully integrated pharmaceutical network and to explore opportunities in Open Innovation is also becoming more evident.  Lilly’s Drug Discovery (TargetD2) and Phenotypic Drug Discovery (PD2) programmes provide an array of primary assays and secondary assays to characterise the biological activity of compounds from external investigators.  Roche have set up a collaborative scheme in which they provide a 100K library of diverse compounds for use at academic centres involved in new target research.   Pfizer have set up a “Centers for Therapeutic Innovation” initiative which is dedicated to establishing global partnerships between itself and Academic Medical Centres to transform research and development through translational medicine.  GlaxoSmithKline have recently opened the door to clinical data sharing with the release of more data from its clinical trials that could provide unprecedented opportunities to understand disease biology and drug effects.  These examples are by no means comprehensive but go some way to illustrating some of the approaches to build productive links between industry and academia.

In addition, a number of precompetitive consortia have been formed to bridge between industry and academia with the aim of tackling some of the larger scientific themes.  An example is the Structural Genomics Consortium based in both Toronto and Oxford in which academic groups and pharmaceutical companies are working together to develop genuinely useful probes for novel epigenetic targets that will be made openly accessible to the academic and industrial community.  The aim is to help define the role of protein targets in disease systems and thus elucidate which of the targets in the epigenome have the most therapeutic potential. The first example probe to emerge from this consortium was the JQ-1 probe that supported the validation of bromodomain-containing protein 4 (BRD4) as a potential target for NUT midline carcinoma. Since then an array of new chemical probes and X-ray structures of additional epigenetic targets have been delivered and confirm the potential for this type of open innovation model. It is likely that other precompetitive consortia of this type will continue to emerge to cover additional areas of potential target space and it will be fascinating to see how such collaborative endeavours develop over the coming years.

Future perspectives

The pharmaceutical industry has changed dramatically over the past years and so with it the role of the Medicinal Chemist.  No longer is our remit restricted to SAR generation and it is incumbent upon us to use our curiosity and innovation to deliver broader solutions across the drug discovery portfolio.  Two things need happen to deliver a positive Phase III result; a compound must be safe and must be efficacious.  The role of Medchem to drive and champion new technologies that predict and assess safety in the pre-clinical setting will become more and more essential in years to come as clinical failures due to safety are just not a business-viable option.   The compound must also be efficacious requiring the target to be correct and the mechanistic horsepower sufficient to drive the desired biological response.  Medicinal chemistry need to be part of the decision-making process when a biological target is selected and the data generated utilising chemical genetics or chemical biology probes should drive increased confidence in the target choices made.

Scientific collaborations will become more commonplace between Pharma partners and academia and the role of consortia more prominent.  The most fruitful collaborations will be built on a shared vision, great science and the recognition that building partnerships can take a certain amount of time and patience.   The role and extent of pre-competitive research will also become key as Pharma and academia alike work together up to and potentially including clinical Proof of Concept.  This would mean both our scientific breakthroughs and disappointments could be shared communally and the same mistakes not made twice.  It will be interesting to see the level of uptake of this new method of working and the solutions that are found to keep it profitable for all parties concerned.

It is both a challenging and exciting time for MedChem.  New areas of science are opening up and we need to be at the forefront, alongside our Biology colleagues, to harness these opportunities and maximise our impact in the Drug Discovery world.

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References

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Addresses of the authors:

Dr. Sarah Skerratt
Pfizer Neusentis
The Portway Building, IPC 300
Granta Park, Cambridge CB21 6GS
Email: sarah.skerratt@pfizer.com

Dr. R. Ian Storer
Pfizer Neusentis
The Portway Building, IPC 300
Granta Park, Cambridge CB21 6GS
Email: ian.storer:pfizer.com