Forward chemical-genetic discovery

Fig. 6-24 Future challenges for forward chemical-genetic discovery of probes of biological mechanisms.

To summarize, as shown in Table 6-2, in a forward chemical-genetic screen, scientists start with a phenotype to find the protein or proteins responsible for it, and in a reverse chemical-genetic screen, the starting point is a protein of interest. Completing the trio of arrows in the discovery cycles in both cases provides valuable tools for the dissection of biological systems and mechanisms. 

Schreiber gave another example where he successfully employed diver-sify-oriented synthesis for the discovery of transcription factor inhibitors (Koehler, Shamji, and Schreiber, 2003). Khersonsky and coworkers linked forward chemical genetics techniques with chemical microarrays. After phenotypic screening, triazine core-containing affinity matrices as micro-arrays were used (Khersonsky et al., 2003 Khersonsky and Chang, 2004). 

In this section, the discovery of small molecules for the interrogation of biological mechanisms will be described. An appropriate small molecule tool may be discovered either on the basis of modulation of the activity of a specific protein (reverse chemical genetics. Section 1.3.1) or its phenotypic effect (forward chemical genetics. Section 1.3.2). Emphasis will be placed on the approaches that may be used to discover useful small molecule tools, and the insights into biological mechanisms that may be accrued. 

Discovery of Small Molecule Probes Using the Forward Chemical Genetic Approach... 

As forward chemical genetic screens are commonly performed in the context of a human disease hypothesis, a blurred line between probe development and drug discovery can potentially create incentives to limit the use of discovered compounds through patent protection. While the intent of chemical biology is not to stifle therapeutic development but conversely to enable future... 

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