This concept has the ability to accelerate progress particularly when working within proven families of drugable targets where the screening of a dozen or more members yields rapid information about how to achieve selectivity and provides the tools to understand added therapeutic applications in a very targeted way as illustrated in Figure 9 below and as anticipated by chemical genomics. Absolutely key to this approach is high data quality from screening runs conducted at very high capacity - a key area of study exemplified in a study of caspases in microfluidic environments (19).
Creating Connectivity- Gene Families
Some implications/Suggestions for consideration: 1. Make an organizational investment in gene families that can leverage the therapeutic scope of your organization and its web of collaborators; 2. Build the informatics tools and that allow the mining of elusive data and the identification of connections that form the basis of an integrative biology approach which builds on islands of data and knowledge; 3. Build up technologies that allow full access to similarly configured assays and inhibitor x-ray crystal structure determinations across different families and selective hits so that progress is accelerated, and 4. Leverage contacts with the academic and venture communities in probing for the physiologic role of unproven genes using the chemical genomic tools developed by this approach
CAN WE AFFORD TO FRONT LOAD THE HIT TO LEAD SEGMENT OF DISCOVERY - WILL IT TAKE TOO MUCH TIME?
The levels of dollar investment in failed candidates are enormous, as illustrated in Figure 10 (24). Any changes that promise a two- or even four-fold improvement in success rates can easily justify tens and even hundreds of millions of dollars of investment. As to time cost, it only feels costly to take extra time at the outset to refine the scope of our hits. If we sum the time lost in serial attempts to enhance drugability and the time cost in reloading after failures, extra months spent at the front end will actually save time when viewed from a business systems perspective. The time savings from speedier development of the resulting highly drugable leads will more than make up for the up front investments in hit diversity and elaboration and the ability to return to a broad, well developed IP base in the event of the still inevitable failures. These kinds of benefits are not beyond our reach if we use our new found scale, capacity and chemistry and new assemblies of biological screens, as outlined in this chapter.
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