dc.contributor.author | McGrath, S | |
dc.contributor.author | Tortorici, M | |
dc.contributor.author | Drouin, L | |
dc.contributor.author | Solanki, S | |
dc.contributor.author | Vidler, L | |
dc.contributor.author | Westwood, I | |
dc.contributor.author | Gimeson, P | |
dc.contributor.author | Van Montfort, R | |
dc.contributor.author | Hoelder, S | |
dc.date.accessioned | 2020-06-15T10:51:23Z | |
dc.date.issued | 2017-07-18 | |
dc.identifier.citation | Chemistry (Weinheim an der Bergstrasse, Germany), 2017, 23 (40), pp. 9577 - 9584 | |
dc.identifier.issn | 0947-6539 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3739 | |
dc.identifier.eissn | 1521-3765 | |
dc.identifier.doi | 10.1002/chem.201700747 | |
dc.description.abstract | 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 Kd 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. | |
dc.format | Print-Electronic | |
dc.format.extent | 9577 - 9584 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | WILEY-V C H VERLAG GMBH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Humans | |
dc.subject | Peptides, Cyclic | |
dc.subject | Oligopeptides | |
dc.subject | Repressor Proteins | |
dc.subject | Magnetic Resonance Spectroscopy | |
dc.subject | Binding Sites | |
dc.subject | Amino Acid Sequence | |
dc.subject | Protein Conformation | |
dc.subject | Protein Binding | |
dc.subject | Thermodynamics | |
dc.subject | Mass Spectrometry | |
dc.subject | Co-Repressor Proteins | |
dc.title | Structure-Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1. | |
dc.type | Journal Article | |
rioxxterms.versionofrecord | 10.1002/chem.201700747 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Chemistry (Weinheim an der Bergstrasse, Germany) | |
pubs.issue | 40 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Hit Discovery & Structural Design | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicinal Chemistry 4 (including Analytical Chemistry) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Structural Biology/Hit Discovery & Structural Design | |
pubs.publication-status | Published | |
pubs.volume | 23 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Medicinal Chemistry 4 (including Analytical Chemistry) | |
icr.researchteam | Hit Discovery & Structural Design | |
dc.contributor.icrauthor | Van Montfort, Robert | |
dc.contributor.icrauthor | Hoelder, Swen | |