Structural highlights
FunctionTLE1_HUMAN Transcriptional corepressor that binds to a number of transcription factors. Inhibits NF-kappa-B-regulated gene expression. Inhibits the transcriptional activation mediated by FOXA2, and by CTNNB1 and TCF family members in Wnt signaling. The effects of full-length TLE family members may be modulated by association with dominant-negative AES. Unusual function as coactivator for ESRRG.[1] Publication Abstract from PubMedTLE1 is an oncogenic transcriptional co-repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein-protein interaction represents a putative cancer target but no small molecule inhibitors have been published for this challenging interface. In this manuscript, we report the structure enabled design and synthesis of a constrained peptide inhibitor of TLE1. Our design featured introduction of a four carbon atom linker into the peptide epitope found in many TLE1 binding partners. We developed a concise synthetic route to a proof of concept peptide cycFWRPW. Biophysical testing by ITC and thermal shift assays showed that whilst the constrained peptide bound potently, it had an approximately five fold higher Kd than the unconstrained peptide. Our co-crystal structure suggested that the reduced affinity is likely due to a small shift of one side-chain compared to the otherwise well conserved conformation of the acyclic peptide. Our work describes a constrained peptide inhibitor that may serve as the basis for improved inhibitors. Structure Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1.,McGrath S, Tortorici M, Drouin L, Solanki S, Vidler L, Westwood I, Gimeson P, vanMontfort R, Hoelder S Chemistry. 2017 Mar 22. doi: 10.1002/chem.201700747. PMID:28326635[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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