Preface

Kinases, also known as phosphotransferases, are a family of enzymes that

catalyse the transfer of a phosphate from donor molecules such as ATP

(adenosine triphosphate) to their specific substrates. Over 500 protein kinases

have now been identified in the human kinome, which have been the main

focus of Kinase Drug Discovery in recent years. There are currently around 13

FDA-approved small molecule kinase inhibitors (listed at the end of this

Preface) along with a handful of biological therapeutics, with over 500

additional small molecules in active development targeting kinases. These

agents have in turn delivered very significant benefits to patients that can be

measured as significant life extension or significant improvement in quality of

life in diseases like cancer and inflammation. The kinase family has therefore

been a rich source of new targets and opportunities for the pharmaceutical

industry but has also presented significant challenges. Due to the sequence and

structural similarity of kinases in the kinase domain, specifically the ATP

binding site, targeting kinases in drug discovery was initially assumed by many

people to be extremely difficult, if not impossible. The affinity of kinases to

ATP was also a concern, which was often manifested in large potency drop-

offs from enzyme to cell assays. However, selective kinase inhibitors were first

discovered by exploiting amino acids around the ATP pocket which are not in

contact with ATP. The similarity of kinases in the immediate vicinity of the

ATP site but increasing differences outside of this region has resulted in an

explosion of interest by medicinal chemistry over the last decade. The mining

of activity data for compounds across increasing numbers of kinases along

with the increasing success in solving X-ray crystal structures have allowed

kinases to be approached by drug discovery scientists as a target class. A

variety of lead generation approaches have been specifically tailored to exploit

this family such as the re-profiling of leads against different kinase targets,

RSC Drug Discovery Series No. 19

Kinase Drug Discovery

Edited by Richard A. Ward and Frederick Goldberg

# Royal Society of Chemistry 2012

Published by the Royal Society of Chemistry, www.rsc.org

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scaffold or template-hopping along with structural hybridizations and SAR

transfer. Methods of screening compounds and identifying leads have also

evolved with new assay formats and approaches such as fragment-based lead

generation (FBLG). In addition to the significant focus around targeting the

active form of the kinase through direct competition with ATP, inactive

conformations of kinases have also been targeted. Kinases have been observed

to have a variety of inactive conformations through movement of the

conserved DFG-loop and c-helix which has increased the diversity of chemical

opportunities. Targeting such conformations can increase selectivity and

potentially overcome the large enzyme to cell potency drop-offs from direct

competition with ATP. There may also be kinetic advantages to targeting

inactive conformations, where slow off rates (long residence times) have been

linked to enhanced in vivo efficacy. Novel allosteric pockets have also been

identified which can be targeted by a small molecule in the kinase (and

adjacent) domains along with compounds binding to the kinase-ATP complex.

Throughout this book we aim to summarise the challenges and the

opportunities which the kinase family has presented to drug discovery

scientists over recent years. One view is that the protein kinase target class

has now largely been exploited. However, feedback from the clinic is likely to

result in significant additional learning and opportunities over the coming

years. Rather than focussing on case studies of specific targets we have aimed

to cover broader themes. In particular, our aim for this book is to focus on the

‘hot topics’ in kinase drug discovery which we believe will be key areas in the

coming years.

Rather than seeing the conserved nature of the ATP site as a hindrance,

David Drewry and co-authors (Chapter 1) examine how medicinal chemists

are exploiting our increased understanding of the kinome by looking at cross-

reactivity and tuning out broader kinase activity. Also described is a summary

of available assays and methods to understand the selectivity of kinase

inhibitors. In Chapter 2 Iain Simpson goes on to review the cutting edge

approaches to identifying hits against kinases, then Martin Swarbrick covers

the issues that medicinal chemists face when optimising those leads into

candidate drugs. In a related topic Walter Ward (Chapter 4) then covers the

different mechanisms available to targeting kinase inhibition and how to

exploit them to drive SAR. One particular hot topic of kinase drug discovery is

how we should respond to clinical feedback. One way we can apply this

feedback in drug discovery is covered by Jack Bikker in Chapter 5, reviewing

kinase mutations and resistance. Whereas the primary focus of the first 5

chapters is on the dominant theme of protein kinases for oncology indications,

Chapters 6-9 focus on other diverse areas of interest to drug discovery. Jeroen

Verheijen and co-authors cover the progress made and future opportunities

within non-protein kinases in Chapter 6, focussing on sugar, nucleoside and

lipid kinases. Andrew Ratcliffe then covers non-oncology applications for

kinase inhibitors in Chapter 7. Although the majority of kinase inhibitors in

development are targeted at oncology indications, important opportunities

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remain in non-oncology disease indications where kinase inhibitors have the

potential to address other significant unmet medical needs. Kinase activators

are outside the scope of Andrew Ratcliffe’s review, but are picked up by Kevin

Guertin who presents a case study of allosteric activators of glucokinase for

the treatment of type 2 diabetes in Chapter 8. In this chapter he reviews the

history of glucokinase activators and discusses their novel mechanism of

action. Another significant unmet medical need where kinase drug discoverycould have a future impact is in human parasitic diseases. To that end Andrew

Wilks goes beyond the human kinome in Chapter 9, where he discusses the

therapeutic opportunities that the non-human kinomes present and the early

but exciting drug discovery efforts that have been made thus far. To conclude

the book Carlos Garcia-Echeverria has kindly contributed his thoughts on the

future of kinase drug discovery, on such topics as new methods to overcome

resistance, novel mechanisms and pseudokinases.

Although each of these chapters can be read as an individual standalonereview of the topic being covered, there are themes which are picked up in

multiple chapters which allow the readers to review key areas from multiple

authors.

We would like to thank all of the authors and co-authors for their hard work

in contributing the chapters for this book. In particular we would like to

acknowledge their efforts to stay committed to the book during a very

challenging time for drug discovery scientists in industry and academia. The

authors of this book have brought a combined experience of well over 200years in drug discovery research, across dozens of research organisations and

covering multiple disciplines and specialities.

Richard A Ward, PhD, is a Computational Chemist working within the

Oncology iMed at AstraZeneca, Alderley Park, UK

Frederick W Goldberg, PhD, is a Medicinal Chemist working within the

Oncology iMed at AstraZeneca, Alderley Park, UK

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FDA Approved Small Molecule Kinase Inhibitors

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