Chromenopyrazole-Peptide Conjugates as Small-Molecule Based Inhibitors Disrupting the Protein-RNA Interaction of LIN28-let-7.

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. © 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.

Citation

Pascal Hommen, Jimin Hwang, Fubao Huang, Lydia Borgelt, Lisa Hohnen, Peng Wu. Chromenopyrazole-Peptide Conjugates as Small-Molecule Based Inhibitors Disrupting the Protein-RNA Interaction of LIN28-let-7. Chembiochem : a European journal of chemical biology. 2023 Sep 01;24(17):e202300376

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PMID: 37224100

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