Successful stem cell applications could significantly impact the medical fields, where many lives are at stake. However, the translation of stem cells to the clinic could be improved by challenges in stem cell transplantation and in vivo retention...
Chromenopyrazole–peptide conjugates as small‐molecule based inhibitors disrupting the protein–RNA interaction of LIN28–let‐7
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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 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 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.Zum Volltext
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