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Chemical Biology. A bump-and-hole Approach to Engineer Controlled Selectivity of BET Bromodomain Chemical Probes

Baud M, et al., 346(6209):638-41, Science, 2014

The article describes an approach to obtain selective inhibitors for Bromo and Extra-terminal (BET) bromodomain proteins. The BET proteins are important targets due to their roles in transcriptional regulation, epigenetics, and cancer. The authors used a chemical genetic approach to achieve shape complementarity between the bromodomain and a small-molecule inhibitor based on a "bump and hole" strategy. In other words, the bromodomain is mutated to a smaller residue to generate a "hole" on the protein. The mutated protein is targeted with analogs of a known ligand having a sterically bulky group ("bump") that can be accommodated by the pocket engineered on the mutated protein. The BLI experiments helped them to generate a heat map and hence identify BET mutants with similar binding profiles to their respective wild-type protein. An Octet RED 384 system equipped with SA sensors were used to immobilize biotinylated histone H4 peptides.

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