(BQ) Part 2 book “Designing multi-target drugs” has contents: The discovery of lapatinib; identification and optimization of dual pi3k mtor inhibitors; discovery of hdac inhibiting multi target inhibitors; discovery of the anti psychotic drug, ziprasidone; the rational design of triple reuptake inhibitors for the treatment of depression, and other contents. | CHAPTER 11 Combination Agents Versus Multi-Targeted Agents – Pros and Cons JOSE G. MONZON AND JANET DANCEY* National Cancer Institute of Canada, Clinical Trials Group, 10 Stuart Street, Kingston, ON K7L 3N6, Canada *Email: jdancey@ Introduction Although the vast majority of diseases are multi-factorial in nature, most modern drug discovery is based on identifying a drug that acts on a single derangement felt to be involved in disease development or progression. Due to the multi-factorial nature of most diseases, a selective compound for a single target rarely achieves the desired effect and is often combined with standard treatments or other novel targeted agents to improve effectiveness. This could not be truer for novel anti-cancer molecularly targeted therapeutics (MTTs). Most curative cancer treatment is based on identification of effective drug combinations. The success of combinations is likely due to the fact that cancer is a heterogeneous disease among patients and within the same patient. Cancer cells are genotypically and phenotypically complex and adaptive. There may be de novo protective mechanisms that render individual drugs ineffective. In addition, acquired resistance occurs with almost all agents over time unless the therapy is curative. Historically, the goal of cytotoxic agents was to maximize RSC Drug Discovery Series No. 21 Designing Multi-Target Drugs Edited by J. Richard Morphy and C. John Harris r Royal Society of Chemistry 2012 Published by the Royal Society of Chemistry, 155 156 Chapter 11 tumor cell kill. The limited selectivity of conventional cytotoxic cancer drugs was based on their disruption of the frequent cell division and DNA replication of cancer cells relative to most normal cells. Most cytotoxic cancer drugs act by inhibiting synthesis of DNA precursors, damaging the DNA template, or disrupting chromosomal segregation. However, rapidly dividing normal tissues, such as those of the bone marrow,
