Expanded File

Successful Drug

Figure 6: Parallel Optimization Vortex thereby create an intellectual vortex that opens up the opportunities to create a deeper and interconnected experimental base - improving our chances of identifying the truly drugable series for final elaboration. The benefit of starting with multiple chemotypes is that it gives the Discovery team maximum flexibility to recover from unforeseen problems along the development path. In a targeted form, rapidly expanding chemotype space is also key to generating patentable new prototypes capable of meeting the high hurdles for best-in-class, fast follower approaches Clearly, this focus on high capacity parallel optimization requires new tools and, in particular new ways of working and managing this most key step in the discovery process.

Early stage parallel optimization requires the assembly of a series of ultra high capacity technologies including an emphasis on rapid combinatorial expansions of hit series (18-21). It requires new partnerships between Discovery scientists and their colleagues in Drug Safety Evaluation and Pharmaceutical Sciences (formulation, stability, physicochemical properties) in developing well validated new assays which allow one to build in drugability at the stage of hits and early leads. It requires the development of visualization tools which enable us to enhance lead identification though a process of parallel optimization where closed- loop learning, parallel processing and data mining meet to create a vastly richer array of choices leading up to the selection of a lead series (22, 23).

Activity "Spider Diagram"

Figure 7: Multidimensional Optimization of Hits and Leads

"HIT' IDEAL LEADS

Figure 7: Multidimensional Optimization of Hits and Leads

By creating the kind of "spider diagram" (Figure 7) for each of the hits and by expanding a dozen or more hits through several cycles of computer aided diversity expansions; by keeping an eye on the rule of 5, we should be far more likely to settle in on a series with maximum drugability. This is a testable hypothesis, but even if we pick wrong we are in a position to rapidly reload based on intellectual property already created! In addition, with time this investment in high quality multifactorial data sets should also begin to elaborate new and more powerful prospective approaches to building in drugability and the preparation of more targeted, "biased libraries.

Some implications/suggestions for consideration: 1. Change what we measure as progress in early discovery so that it supports the discomfort of not choosing prematurely; 2. Develop combinatorial chemical processes and infrastructure! capacity that allow rapid and diversity driven expansions of a dozen or more hit series through several iterations; 3. Invest in high capacity molecular toxicology AD/ME and pharmaceutics assays and the informatics to enable parallel evaluation of potential to surmount the 5 or 6 most likely hurdles to successful and speedy development; 4. Employ your experience to develop your own scholarship on the effectiveness and productivity of specific tactics and 5. Be specific about the technical implications of the new paradigm and, as a priority, engage webs of collaborators in their solution.

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