Authors: Hommen, Pascal
Title: Design, synthesis, and evaluation of small molecules and associated bifunctional conjugates targeting the protein–RNA interaction of LIN28 and let-7
Language (ISO): en
Abstract: RNAs have evolved as prominent targets to tackle challenging topics in the field of chemical biology and medicinal chemistry. Concomitantly, RNA binding proteins (RBPs) are emerging as a new class of drug targets given the essential regulatory functions of RBPs in deciding cell fates. Despite the increasing understanding of the importance of RBPs, limited chemical tools are available to probe the biological functions of RBPs, which raises the need for the development of effective and selective tool compounds targeting RBPs. The LIN28–let-7 interaction is one of the most well-investigated protein–RNA interactions to date. Due to its association with a poor cancer prognosis, LIN28 is a potential new anticancer target. Among the current collection of reported LIN28 inhibitors, potent molecules with clear mechanisms of inhibition are lacking. Additionally, most reported LIN28 inhibitors were identified via high throughput screening of different formats against molecular libraries that were not tailored to target RBPs. Therefore, there is a need to diversify the discovery approaches for RBP-targeting molecules. In this context, small-molecule-based approaches were adopted to engage the challenging topic of targeting the miRNA-binding protein LIN28. Furthermore, we designed an intriguing bifunctional molecule in which an affinity-enhancing moiety was linked to a known LIN28 small-molecule inhibitor to build bifunctional molecules to improve efficacy. Inspired by a rationale, first established in targeting protein–protein interactions, hotspot amino acids were identified through an analysis of LIN28–let-7 crystal structure and a virtual alanine scan to design the corresponding affinity-enhancing moieties consisting of peptides. Conjugation between the designed peptides and the known LIN28 inhibitors led to enhanced binding affinity. In other approaches, we investigated compounds of three chemical scaffolds intending to study the structural features required for LIN28 inhibition, as well as identifying suitable small molecules to be used in the bifunctional molecule approach. After the initial investigation, chromeno[4,3-c]pyrazoles were used as the small molecule components to be conjugated to a peptide moiety through CuAAC chemistry. After screening for optimal linker length and the amino acid composition of the peptide, compound 111 was identified as a potent bifunctional molecule disrupting the LIN28–let-7 interaction. The resulting novel class of chromenopyrazole–peptide conjugates showed improved properties in comparison with peptide-based probes. Therefore, proving the design strategy of the study and underlining the advantageous properties of conjugated entities over nonconjugated inhibitors
Subject Headings: RNA-binding protein
Protein-RNA interaction
Bifunctional conjugate
Chromenopyrazole inhibitor
Tetrahydroquinoline inhibitor
Pyrrolinone inhibitor
Subject Headings (RSWK): RNA
Medizinische Chemie
Issue Date: 2022
Appears in Collections:Chemische Biologie

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