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.