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 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.