Abstract
Cancer is one of the leading causes of death worldwide. With the increase in life expectancy, the number of cancer cases has reached unprecedented levels. In this scenario, the pharmaceutical industry has made significant investments in this therapeutic area. Despite these efforts, cancer drug research remains a remarkably challenging field, and therapeutic innovations have not yet achieved expected clinical results. However, the physiopathology of the disease is now better understood, and the discovery of novel molecular targets has refreshed the expectations of developing improved treatments. Several noteworthy advances have been made, among which the development of targeted therapies is the most significant. Monoclonal antibodies and antibody-small molecule conjugates have emerged as a worthwhile approach to improve drug selectivity and reduce adverse effects, which are the main challenges in cancer drug discovery. This review will examine the current panorama of drug research and development (R&D) with emphasis on some of the major advances brought to clinical trials and to the market in the past five years. Breakthrough discoveries will be highlighted along with the medicinal chemistry strategies used throughout the discovery process. In addition, this review will provide perspectives and updates on the discovery of novel molecular targets as well as drugs with innovative mechanisms of action.
Highlights
When the nitrogen mustard alkylating agent mechlorethamine reached the market in 1949 as the first anticancer drug, the worldwide life expectancy was 46.8 years (World Population Prospects The 2015 Revision, Kinch 2014)
Ado-trastuzumab emtansine, an antibody-drug conjugates (ADCs) approved within the last five years, is conjugated with a cytotoxic compound that targets tubulin, which is the same mechanism of the cytotoxic agent monomethyl auristatin E conjugated to brentuximab-vedotin. Another class of drugs that debuted in this period consists of the following inhibitors of poly(ADP-ribose) polymerases (PARPs), which are enzymes involved in DNA repair (Beck et al 2017): olaparib, rucaparib and niraparib
Recent clinical trials and Investigational New Drug (IND) applications have shown that targeted therapy is the main focus of current cancer research and development (R&D), in detriment of cytotoxic therapy
Summary
Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, Av. Manuscript received on October 17, 2017; accepted for publication on December 18, 2017
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