Small molecules with tetrahydroquinoline-containing Povarov scaffolds as inhibitors disrupting the Protein–RNA interaction of LIN28–let-7

• Published in: European journal of medicinal chemistry 2022-01, Vol.228, p.114014-114014, Article 114014
• Main Authors: Goebel, Georg L., Hohnen, Lisa, Borgelt, Lydia, Hommen, Pascal, Qiu, Xiaqiu, Lightfoot, Helen, Wu, Peng
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; LIN28 inhibitor; Molecular Structure; Povarov reaction; Protein–RNA interaction; Quinolines - chemical synthesis; Quinolines - chemistry; Quinolines - pharmacology; RNA - antagonists & inhibitors; RNA - chemistry; RNA - metabolism; RNA-Binding protein; RNA-Binding Proteins - antagonists & inhibitors; RNA-Binding Proteins - chemistry; RNA-Binding Proteins - metabolism; Small Molecule Libraries - chemical synthesis; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Structure-Activity Relationship; Tetrahydroquinoline scaffold
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2021.114014

Inhibition of the RNA-binding protein LIN28 and disruption of the protein–RNA interaction of LIN28–let-7 with small molecules holds great potential to develop new anticancer therapeutics. Herein, we report the LIN28 inhibitory activities of a series of 30 small molecules with a tricyclic tetrahydroquinoline (THQ)-containing scaffold obtained from a Povarov reaction. The THQ molecules were structurally optimized by varying the 2-benzoic acid substituent, the fused ring at 3- and 4-positions, and the substituents at the phenyl moiety of the tetrahydroquinoline core. Among the tested compounds, GG-43 showed dose-dependent inhibition in an EMSA validation assay and low micromolar inhibitory activity in a fluorescence polarization-based assay measuring disruption of LIN28–let-7 interaction. Binding mode between GG-43 and the cold shock domain of LIN28 was proposed via a molecular docking analysis. The study provides one of the first systematic analyses on structural features that are required for LIN28 inhibition, and indicates the necessity to develop small molecules with new scaffolds as LIN28-targeting probes and therapeutic candidates. In parallel, this study demonstrates the polypharmacological nature of tricyclic THQ-containing scaffolds accessible through Povarov reactions. [Display omitted] •The most comprehensive and first systematic LIN28 structure-activity relationship study.•30 Tricyclic tetrahydroquinolines were synthesized via the three-component Povarov reaction.•Compound GG-43 is among the most potent LIN28 inhibitors reported to date.•Evaluated molecular mechanism of LIN28-inhibition by GG-43 via docking analysis.