Cancer Drug Design and Discovery

Stephen Neidle

• Publisher: Academic Press
• Year: 2011
• eBook ISBN: 9780080554952
• Topic: Physical Sciences
• Subtopic: Oncology

The ultimate source of information on the design of new anticancer agents, emphasizing small molecules, this newest work covers recent notable successes resulting from the human genome and cancer genomics projects. These advances have provided information on targets involved in specific cancers that are leading to effective medicines for at least some of the common solid tumors. Unique sections explain the basic underlying principles of cancer drug development and provide a practical introduction to modern methods of drug design. Appealing to a broad audience, this is an excellent reference for translational researchers interested in cancer biology and medicine as well as students in pharmacy, pharmacology, or medicinal and biological chemistry and clinicians taking oncology options.* Covers both currently available drugs as well as those under development* Provides a clinical perspective on trials of new anticancer agents* Presents drug discovery examples through the use of case histories

Part I

Basic Principles

Outline

Chapter 1: Modern cancer drug discovery: integrating targets, technologies and treatments

Chapter 2: Preclinical pharmacology and in vivo models

Chapter 3: Clinical trial designs for more rapid proof-of-principle and approval

CHAPTER 1

Modern cancer drug discovery: integrating targets, technologies and treatments

PAUL WORKMAN and IAN COLLINS

Publisher Summary

This chapter aims to capture the sense of excitement and to describe the opportunities and challenges in the discovery and design of molecularly targeted small-molecule cancer drugs. Small-molecule targeted cancer drugs such as imatinib; erlotinib and others discussed in this chapter provide clear proof of concept that significant clinical benefit can be obtained by developing drugs that act on the particular oncogenic abnormalities that are responsible for malignant transformation and progression. Drugging the cancer genome is now a reality. On the other hand, although the importance and utility of the molecularly targeted approach are now well established, cancer is still a formidably complicated disease and many challenges remain to be overcome. The most appropriate strategy for finding small-molecule leads is dependent on the nature of the molecular target and the associated biology. Molecular diagnostics are needed to select animal models and patients that are the most appropriate for assessing the activity of the particular agent. Molecular biomarkers are also absolutely essential to determine proof of concept for modulation of the desired target, and to help determine what is the optimal dose and administration schedule.

We are living through an incredibly exciting era for cancer drug discovery and development – and one that is full of enormous opportunities and challenges. In this chapter we aim to capture the sense of excitement and to describe the opportunities and challenges in the discovery and design of molecularly targeted small-molecule cancer drugs. In particular, we stress the importance of integrating three key themes: targets, technologies, and treatments. First, the molecular targets of contemporary drug discovery projects now reflect our increasing understanding of the genes and pathways that are responsible for the initiation and malignant progression of cancer. We describe different ways in which potential new molecular targets can be considered, validated, and prioritized. Secondly, we highlight the integrated application of a range of powerful drug discovery technologies, including genomics, high-throughput and other compound screening methodologies, and structural biology. We describe the process of multidisciplinary small-molecule cancer drug discovery, and emphasize how the challenges of multi-parameter lead optimization are being met. Thirdly, the new treatments that have been emerging over the last decade are beginning to reflect the success of the new mechanism-based molecular therapeutics that act on cancer-causing targets and that have benefited from technological innovations in drug design. As a result, cancer drugs are leading the way in the development of personalized molecular medicines. We show how the development and use of such treatments depends on the identification of biomarkers to select appropriate patients and to monitor the effects of treatment.

1.1 INTRODUCTION: CHANGING TIMES

Cancer drug discovery has undergone a remarkable series of changes over the last decade. The first generation of cancer drugs were almost all cytotoxic agents. These frequently act by damaging DNA, inhibiting its synthesis or interfering with the mechanics of cell division – for example, by blocking topoisomerases or binding to microtubules (Chabner and Roberts, 2005; Workman, 2005a). Many of these agents were discovered by screening for chemical compounds that were able to kill cancer cells, as with the natural product microtubule inhibitor paclitaxel (Rowinsky et al., 1992). DNA alkylating agents, originally based on sulfur and nitrogen mustards, were structurally modified so as to control their rates of chemical reactivity, leading to drugs such as cyclophosphamide and ifosphamide (Colvin, 1999). Drugs developed in this first, cytotoxic era of cancer drug development were not designed to take advantage of our current knowledge of the genetic and molecular basis of cancer. Nevertheless, many of them were “molecularly targeted,” as in the case of the antifolate thymidylate synthase inhibitors (see Chapter 9), in the sense that they were designed according to the principles of contemporary medicinal chemistry, and in some cases involved the application of structure–activity relationships and X-ray crystallography to a single, defined molecular target (Marsham et al., 1999).

So what has changed so much? First, the molecular targets of contemporary cancer drug discovery projects are very different. They now reflect our increasing understanding of the genes and pathways that are responsible for the initiation and malignant progression of cancer (Workman, 2005b). Secondly, the integrated application of a range of powerful drug discovery technologies has had a major impact (Collins and Workman, 2006a). Thirdly, the new treatments that have been emerging over the last decade are beginning to reflect the success of the new mechanism-based molecular therapeutics that act on cancer-causing targets and that have benefited from technological innovations in drug design. As a result, cancer drugs are leading the way in the development of personalized medicine. This book brings together many of the important aspects of the discovery and design of new cancer drugs, emphasizing small molecules. In this chapter, we provide a scene-setting introduction to, and overview of, modern small-molecule cancer drug discovery, focusing on innovations in targets, technologies, and treatments. As indicated in the title, we will argue that success is dependent on the close integration of these three major themes. First, however, it is useful to assess what progress overall has been made and what the current limitations are. This provides a firm foundation for understanding what needs to be done to move the field forward. Following this we will review the drug discovery process in detail, from the identification of the molecular target through to selection of a drug candidate. Specific examples and case histories will be provided. We end the chapter by drawing some conclusions and taking a look into the future.

1.2 SUCCESSES AND LIMITATIONS

1.2.1 Cytotoxic agents

There have been many notable successes with “conventional,” cytotoxic drug treatments for cancer. The disease exists in a large number of forms, as defined anatomically, under the light microscope, and, more recently, at the molecular level. The effectiveness of drug treatment varies across these different anatomical, histological, and molecular types. Major improvements have been achieved in the treatment of leukemias, lymphomas, testicular cancer, and children’s malignancies, leading to marked increases in survival (www.cancer.org/downloads/STT/Cancer_Statistics_2006_Presentation.ppt). On the other hand, progress has been modest at best in the common adult epithelial tumors. As a result of the limitations of current therapy, cancer remains the second most frequent cause of death in the United States, and seems likely to overtake cardiovascular disease as the most common fatal disease in the near future (Varmus, 2006; www.cancer.org/downloads/STT/Cancer_Statistics_2006_Presentation.ppt). Together with tremendous opportunities afforded by the availability of new targets and technologies, it is the major unmet need of cancer treatment that is driving the enthusiasm for cancer drug discovery.

1.2.2 New molecular cancer therapeutics

Over the last decade it became clear that major gains in survival w...

Table of contents

• Cover image
• Title page
• Table of Contents
• About the editor
• Contributors
• Introduction
• Part I: Basic Principles
• Part II: Methology
• Part III: Drugs in the Clinic
• Part IV: New Agents
• Part V: The Reality of Cancer Drugs in the Clinic
• Glossary
• Index