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Since its
installation in 2003 RAISE has been successfully applied to 60 target
proteins covering various target classes. Two typical case studies are
described below.
 Proterase inhibitor program ( Case A)
Identification of selective Inhibitors against
closely related hydrolytic Enzymes
( Case B) |
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| Protease
inhibitor program |
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| Protease A
was screened against our fragment and leadlike libraries. Various novel
fragments have been identified on the arrays. Detailed data analysis
using our chemobiological database revealed interesting array hit
compounds. Such compounds have been synthesized as soluble, untagged
analogs and validated in subsequent primary and secondary assays. These
results built the basis for an in house project resulting in low
nanomolar compounds active in animal in vivo models. Along with
efficacy an opportunity for broad IP scope was laid out.
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Protease A
The binding pattern of protease A evolving from the fingerprinting
experiments against a 9216 leadlike compound array is visualized by the
Jarray software. The color expresses SPR signal strength and is a
measure for relative binding strength of the protein to the immobilized
array compound. Grey spots are control ligands used for internal
quality control. |
Summary
The case studies show that Graffinity's fragment based drug
discovery process with the
underlying fragment screening and microarray technology allows for
early selectivity and
druggability analysis and provides chemical information at very early
stage in the discovery process.
RAISE is a highly promising approach for the rapid discovery and
optimisation of such small molecules. Starting from low affinity
compounds, nanomolar high affinity compounds can be generated. |
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Fragment screening applied
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Novel fragments identified
• SAR built upon fingerprinting data
• Class of highly potent, low nanomolar
inhibitors identified
• Efficacy in in vivo animal models
• patent applications filed
• Many more IP opportunities |
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