CHAPTER 14 – MECHANISM-BASED HIGH-THROUGHPUT SCREENING FOR NOVEL ANTICANCER DRUG DISCOVERY

The chapter focuses on the role of mechanism-based high-throughput screening (HTS) in contemporary drug discovery of small-molecule cancer drugs. During the last decade, HTS has rapidly developed into a technology-dependent scientific discipline that relies heavily on the use of miniaturized automated assays to achieve huge screening rates. Widespread implementation of this key component has been driven by the success of genomic approaches for novel drug target identification and validation. HTS also provides the means of evaluating large numbers of compounds available in various compound collections, and those provided by combinatorial and parallel synthesis. The growth of HTS has been fueled by rapid concurrent innovations in molecular biology, assay technologies and equipment, as well as automation and information technology. Blackbox screening against whole cancer cells has provided most of the currently useful but limited agents. The NCI 60-cell panel screening operation represents an upgrade of traditional cell screening with the potential to build in a molecular mechanistic component. Intelligent screening against specific molecular targets represents a major step forward in the race for more selective anticancer agents. HTS is always in a state of transition as improvements in technology, and the development of novel instrumentation is an ongoing and inevitable process linked to innovations in other scientific disciplines.

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