Nuclear receptors (NRs), such as glucocorticoid receptor (GR), are ligand-inducible transcription factors that regulate gene expression by recruiting protein complexes to DNA. NRs are important therapeutic targets which, historically, are modulated with small molecules that allosterically recruit transcription cofactors. However, this regulatory pathway collapses in many diseases with mutated NRs. Alternatively, bifunctional small molecules that can directly control cofactor recruitment would provide an alternative pathway for regulation. As a proof of principle, a collection of bifunctional molecules were designed, synthesized and used to recruit the potent transcriptional activator VP16 to GR. VP16 recruitment results in higher levels of transcriptional activation than classical GR agonists and can completely override the intrinsic function of classical GR antagonists. We are currently exploring bifunctional ligands containing histone deacetylase (HDAC) inhibitors to recruit endogenous transcriptional corepressors. My independent career will focus on the discovery of new chemical ligands for these and other histone modifying cofactors.

Controlling recruitment of transcriptional complexes with bifunctional small molecules

244th National Meeting (2012)

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