Trisubstituted Pyrrolinones as Small-Molecule Inhibitors Disrupting the Protein–RNA Interaction of LIN28 and Let-7

Abstract

Modulation of protein–RNA interaction (PRI) using small molecules is a promising strategy to develop therapeutics. LIN28 is an RNA-binding protein that blocks the maturation of the tumor suppressor let-7 microRNAs. Herein, we performed a fluorescence polarization-based screening and identified trisubstituted pyrrolinones as small-molecule inhibitors disrupting the LIN28– let-7 interaction. The most potent compound C902 showed dose-dependent inhibition in an EMSA validation assay, enhanced thermal stability of the cold shock domain of LIN28, and increased mature let-7 levels in JAR cells. The structure–activity relationship study revealed key structural features contributing to either PRI inhibition or stabilization of protein–protein interaction (PPI). The pyrrolinones identified in this study not only represent a new class of LIN28-binding molecules that diversify the limited available LIN28 inhibitors but also represent the first examples of small molecules that showed substituent-dependent PRI inhibitory and PPI activating activities.

Reaction of Hetareno[e]pyrrole‐2,3‐diones with Thiols: An Approach to Two Distinct 5‐Thio‐Substituted Pyrrole‐2‐one Derivatives

“…3‐Hydroxy‐1,5‐dihydro‐2 H ‐pyrrol‐2‐ones have become the focus of attention in medicinal chemistry in the last years [1–4] . For example, 3‐hydroxy‐1,5‐dihydro‐2 H ‐pyrrol‐2‐ones were found to be valuable antibacterial scaffolds including methicillin‐resistant Staphylococcus aureus [5–7] .…”

Research progress on RNA−binding proteins in breast cancer

“…By changing the substituents of 2-Benzoic acid, fused rings at positions 3 and 4, and the substituents of phenyl part of tetrahydroquinoline core, the structure of THQ molecule has been optimized, which can be used as inhibitors to destroy the protein-RNA interaction of LIN28-let-7 ( 96 ). Trisubstituted pyrrolidone can also act as a small molecule inhibitor to destroy the protein-RNA interaction between Lin28 and let-7 ( 97 ). In addition, C1632 is a small molecule inhibitor of LIN28, which can increase let-7 level, reduce PD-L1 and inhibit a variety of cell growth ( 97 ).…”

“…Trisubstituted pyrrolidone can also act as a small molecule inhibitor to destroy the protein-RNA interaction between Lin28 and let-7 ( 97 ). In addition, C1632 is a small molecule inhibitor of LIN28, which can increase let-7 level, reduce PD-L1 and inhibit a variety of cell growth ( 97 ). Furthermore, the inhibitor TPEN can make the zinc finger domain of LIN28 unstable ( 98 ) ( Figure 6 ).…”

RNA: Opening New Doors in Medicinal Chemistry, a Special Issue

“…In addition to targeting RNAs with small molecules, RNA-binding proteins and RNA-modifying enzymes are also emerging as new therapeutic modalities. , Contributions from the laboratories of Peng Wu and Jordan Meier provide new insights into these areas of RNA-targeted drug discovery. The Wu lab from the Max Planck Institute reports a new class of small molecule inhibitors of Lin28 providing new chemical matter for developing antagonists of its interaction with the microRNA, let-7 . The Meier lab from the National Cancer Institute describes a valuable study aimed at evaluating a putative chemical probe targeting the RNA acetyltransferase NAT10 .…”

“…The Wu lab from the Max Planck Institute reports a new class of small molecule inhibitors of Lin28 providing new chemical matter for developing antagonists of its interaction with the microRNA, let-7. 38 The Meier lab from the National Cancer Institute describes a valuable study aimed at evaluating a putative chemical probe targeting the RNA acetyltransferase NAT10. 39 Through their careful studies, they demonstrate that remodelin should not be used as a specific inhibitor of NAT10, providing useful data for researchers in the field.…”