Chromenopyrazole−Peptide Conjugates as Small‐Molecule Based Inhibitors Disrupting the Protein−RNA Interaction of LIN28‐ let‐7
Abstract: Targeting the protein−RNA interaction of LIN28 and let‐7 is a promising strategy for the development of novel anticancer therapeutics. However, a limited number of small‐molecule inhibitors disrupting the LIN28‐let‐7 interaction with potent efficacy are available. Herein, we developed a novel LIN28‐inhibiting strategy by targeting selective hotspot amino acids at the LIN28‐let‐7 binding interface with small‐molecule‐based bifunctional conjugates. Starting from reported small‐molecule LIN28 inhibitors, we identified a feasible linker‐attachment position after performing a structure‐activity relationship exploration based on the LIN28‐targeting chromenopyrazoles. In parallel, a virtual alanine scan identified hotspot residues at the protein−RNA binding interface, based on which we designed a set of peptides to enhance the interaction with the identified hotspot residues. Conjugation of the tailor‐designed peptides with linker‐attached chromenopyrazoles yielded a series of bifunctional small‐molecule‐peptide conjugates, represented by compound 83 (PH‐223), as a new LIN28‐targeting chemical modality. Our result demonstrated an unexplored rational design approach using bifunctional conjugates to target protein−RNA interactions.
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Erschienen in
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Chromenopyrazole−Peptide Conjugates as Small‐Molecule Based Inhibitors Disrupting the Protein−RNA Interaction of LIN28‐ let‐7 ; day:27 ; month:07 ; year:2023 ; extent:12
ChemBioChem ; (27.07.2023) (gesamt 12)
- Urheber
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Hommen, Pascal
Hwang, Jimin
Huang, Fubao
Borgelt, Lydia
Hohnen, Lisa
Wu, Peng
- DOI
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10.1002/cbic.202300376
- URN
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urn:nbn:de:101:1-2023072815234390158043
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
- 14.08.2025, 11:00 MESZ
Datenpartner
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Beteiligte
- Hommen, Pascal
- Hwang, Jimin
- Huang, Fubao
- Borgelt, Lydia
- Hohnen, Lisa
- Wu, Peng
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