Structure-Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1.
Van Montfort, R
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TLE1 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. Herein, the structure-enabled design and synthesis of a constrained peptide inhibitor of TLE1 is reported. The design features the introduction of a four-carbon-atom linker into the peptide epitope found in many TLE1 binding partners. A concise synthetic route to a proof-of-concept peptide, cycFWRPW, has been developed. Biophysical testing by isothermal titration calorimetry and thermal shift assays showed that, although the constrained peptide bound potently, it had an approximately five-fold higher K<sub>d</sub> than that of the unconstrained peptide. The co-crystal structure suggested that the reduced affinity was likely to be due to a small shift of one side chain, relative to the otherwise well-conserved conformation of the acyclic peptide. This work describes a constrained peptide inhibitor that may serve as the basis for improved inhibitors.
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Magnetic Resonance Spectroscopy
Amino Acid Sequence
Medicinal Chemistry 4 (including Analytical Chemistry)
Hit Discovery & Structural Design
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Chemistry (Weinheim an der Bergstrasse, Germany), 2017, 23 (40), pp. 9577 - 9584