Target discovery and validation is perhaps the most critical discipline in the entire pharmaceutical research and development value chain. Where you start from is critically determining the success or failure of projects and selecting the “wrong” target, one that does not modify a disease in the desired way typically equates to late stage, expensive failures in clinical phase II (proof‐of‐concept) studies and beyond!

Although – over the recent decades – there has been significant progress in reducing the so‐called “technical risks” associated with pharmaceutical projects through, e.g., improved understanding, prediction and measurement of drug‐related DMPK (drug metabolism and pharmacokinetics), physicochemical properties, drug‐likeness, toxicity or target engagement, and elicitation of downstream pharmacology (via biomarkers type 1 and 2), with many diseases we still lack a detailed understanding about the prospect of modulating a target or pathway to positively affect or even cure a disease in humans. A good example comes from recent failures in the Alzheimer's disease field, where modulating the “amyloid” cascade was long thought to be the holy grail in finding a medicine for this devastating disease, based on a thorough genetic understanding and validation of the relevance of this target. Although a plethora of clinical candidates (small molecules, antibodies, and vaccines) have been tested in recent years, each one of them has missed the primary end points in late‐stage clinical trials and did not result in slower disease progression. How can we avoid late‐stage clinical failures, improve Research and Development productivity, and speed up the delivery of truly innovative medicines and cures for patients in need? A lot of answers to these questions need to be asked while selecting the right target and pathway to work on while a new project is started.

As a consequence of the described failures, the field of target discovery and validation has undergone significant paradigm changes in the recent years, a few of them are listed here:

• The importance of genetic validation of a target/pathway to increase its disease relevance

  With the advent of measuring human DNA sequences fast, reliably and cost efficiently, and genotyping (the investigation of differences in the sequences) broader patient populations and comparing them to healthy populations has been one of the key pillars for the identification of “genetically validated” targets in the hope to increase the odds for clinical success both by improving the degree of target validation and by better stratifying patients likely benefitting from a targeted therapy against this target/pathway. As one of the first genetically validated targets, mutations of the sodium channel subtype NaV1.7 have been found to provoke congenital insensitivity to pain in humans.

• Disease understanding: from the “soup approach” to a detailed understanding of disease pathology

  While only a few years ago drug discovery in many diseases relied heavily on general assumptions such as “increase or block protein A throughout the entire human system to improve a disease,” today we increasingly believe that a successful therapy must be highly specific in tackling a specific target only at a certain compartment of the human body or even down to selectivity at the cellular level. Personalized medicines for a highly stratified patient population (often rare diseases) or even for an individual patient have delivered innovative medicines, while demonstrating high speed to market. A detailed understanding of the disease pathology and associated targets along with a deep understanding in which compartments and cells the drug needs to interfere is today believed to be a key for success.

• The renaissance of phenotypic screening and advances in automation

  With the desire to identify targets and pathways truly relevant in “authentic” disease conditions and prompted by late‐stage clinical failures because of insufficient efficacy (as described above), one approach taken to frontload that risk was to employ phenotypic screens in highly relevant systems such as whole cells (native or induced pluripotent stem cells), as well as two‐ or three‐dimensional organoids. A whole discipline coined chemical biology has been created around this concept, and a key step is to deconvolute the targets once a change in phenotype in the desired manner (e.g. decrease of survival in cancer cell lines) has been observed. Advances in automation as well as the advent of optogenetics have enabled a higher throughput screening capacity of those “high‐content” assays, making them useful tools for target identification.

• Target discovery and validation has become a truly multidisciplinary field strongly driven by medicinal chemists

  Although target identification and validation has been traditionally a discipline dominated by biologists and pharmacologists, it is today truly a multidisciplinary team work, with the medicinal chemists being one of the key drivers in the team for identifying and validating novel targets that will work in clinical trials.

Alleyn Plowright and his team take on this important discipline both from the view of a medicinal chemist and from the view of the adjacent, critical disciplines. It is in our view a unique opportunity to learn from true experts in the field on not only the concepts and strategies but also to learn from the practical examples and case studies presented. The book is logically split into chemical‐based approaches, biology‐based approaches, and informatics‐based approaches and provides deep, concise, and up‐to‐date answers to all questions the reader might have.

The editors would like to cordially thank Alleyn and the entire team of authors, as well as Frank Weinreich and the Wiley team for getting this project so quickly from concept to production, as we are hopeful that it will fill a large gap and be widely appreciated.

June 2019

Diseases impacting human health are prevalent, and ones affected by lifestyle or age are on the rise throughout the world. Despite many drugs and treatments being available to patients, there is still massive unmet need, and those affected are waiting for new treatment options to improve their and their families' lives. As researchers pushing the boundaries of science, developing novel technologies, discovering the unknown, and creating new treatment options enables us to have a hugely positive impact on society and the lives of people.

Unfortunately discovering new medicines is fraught with difficulties and too infrequently successful. High rates of attrition in clinical trials and the associated high cost of developing a new medicine is a huge problem for drug discovery. Only 10% of molecules nominated as drug candidates that undergo initial phase I clinical trials are successful in transitioning through further phases of clinical development to complete regulatory approval and treat patients who are in need [1]. This unsatisfactory figure does not even include the projects that do not reach the drug candidate stage. If we could improve the drug discovery process and success rates, there is potential to have a massive impact on the lives of patients and society as a whole.

The major challenges and reasons for failure of clinical trials have been well documented with the most frequent reason being lack of efficacy or lack of differentiation of the development candidate over the current standard of care for the disease being treated [2,3]. This is often due to inadequate target validation in the preclinical phases of drug discovery. On top of this, major bottlenecks we face are how to discover new biological targets and pathways relevant to human disease and the overall lack of validated targets in emerging areas of biology. However, science and technology are evolving at such a rapid pace that they are providing a wealth of opportunities for scientists across all fields of research and clinical medicine to contribute to the discovery of novel targets relevant to human disease. In addition, they are providing the necessary tools to more effectively validate these targets as well as understand the mechanisms of action of molecules in the early phases of drug discovery. Taking advantage of these tools will ensure that we focus our efforts and resources on those targets and mechanisms of action with the greatest probability of success to deliver drugs to the people who need them the most, the patients.

Drug discovery is truly a multidisciplinary endeavour. Scientists from different backgrounds and areas of science, informatics, and engineering need to come together, collaborate, and be curious how to utilize each other's diverse knowledge and capabilities to find the best solutions. Medicinal chemists have a key role to play in this along with chemical biologists, data scientists, chemo‐ and bioinformaticians, biologists, clinicians, and other disciplines. We need to continue to come together, join forces, and drive new ideas and innovation to translate novel science and discoveries into new medicines. Pharmaceutical companies, biotech companies, academia, and technology companies need to continue to forge collaborations and work together on solving critical questions to help us all drive forward. Good ideas can come from anywhere in the world, and working together will accelerate the discovery of novel validated targets that can be prosecuted with the armoury of therapeutic modalities we now have at our disposal. With the discovery of new modalities such as proteolysis targeting chimeras (PROTACs), clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and diverse small to large molecule conjugates as well as new screening technologies to expand chemical space such as DNA‐encoded libraries or cryo‐electron microscopy (cryo‐EM) and X‐ray crystallography of membrane‐bound proteins to understand the proteins and complexes we are aiming to modulate will enhance our ability to tackle challenging targets and understand mechanisms of action. All in all this provides many opportunities and makes it such an exciting time to work in the drug discovery arena.

This book is written by experts from academia and industry to highlight a range of techniques and approaches that are continuing to develop and provide utility and impact to help us all discover and validate novel biological targets. The aim of the book is not to be an exhaustive resource but rather to highlight diverse approaches and show the impact of new technologies on the discovery of new biological targets and in target validation studies and how these methods can support academic and drug discovery scientists in their target discovery and validation research. The book will describe both well‐used and novel technologies and showcase recent examples where the methods have been applied. The chapters will be separated into chemistry‐based approaches, biology‐based approaches, and informatics‐based approaches to highlight the range of techniques available and how multidisciplinary these studies are. Each of the approaches shown is complementary and has the ability to significantly impact target discovery and target validation, and a combination of approaches will most often be required to speed up and make this research more effective.

I would like to thank all of the authors for taking their time to share their knowledge and help us all increase our understanding of these important approaches and sharing tips on how we can apply them most effectively to increase our success with target discovery and validation.

Drug discovery is a challenging, innovation‐driven, and large endeavour, and increasing our effectiveness in discovering and validating biological targets for human disease can increase our chances of success in delivering new medicines to patients to cure disease.

References

1. 1 Hay, M., Thomas, D.W., Craighead, J.L. et al. (2014). Clinical development success rates for investigational drugs. Nat. Biotechnol. 32: 40–51.
2. 2 Arrowsmith, J. (2011). Trial watch: phase III and submission failures: 2007–2010. Nat. Rev. Drug Discovery 10: 87.
3. 3 Cook, D., Brown, D., Alexander, R. et al. (2014). Lessons learned from the fate of AstraZeneca's drug pipeline: a five‐dimensional framework. Nat. Rev. Drug Discovery 13: 419–431.