Tools for fragment based drug discovery

Bromodomains

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BROMODOMAINS

PCAF & GCN5

bromodomains-2Bromodomains (BDs) are small, so-called epigenetic readers that are modules that are involved in protein-protein interactions. There are 8 families of BDs presently recognized. Many BDs selectively bind acetylated Lysine residues in target proteins. However, the biology of many BDs remains to be clarified and therefor setting up biological or biochemical screens for hit discovery can be challenging. The BET family of BDs have garnered the most attention to date with BET inhibitors having made their way to the clinic where they are showing great potential.

ZoBio teamed with the SGC in Oxford, UK to screen for inhibitors to the highly homologous BDs of GCN5 and PCAF, members of family 1. Inhibitors of PCAF could have utility as anti-HIV reagents and other possible indications. The ZoBio fragment library was screened using TINS and hits with novel structures were confirmed using Biacore and protein observed NMR. The crystal structures of several fragments of our fragment hits bound to the PCAF BD have been elucidated, as shown above.

In this project numerous validated, novel, ligand efficient starting points are available with full structural support from both X-ray crystallography and NMR. Moreover, these results demonstrate our ability to rapidly generate novel hits for essentially any BD and provide structural support using 2 independent methods for maximal robustness.


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