N-Biphenyl Pyrrolinones and Dibenzofurans as RNA-Binding Protein LIN28 Inhibitors Disrupting the LIN28- Let-7 Interaction

Lydia Borgelt; Lisa Hohnen; Jakob S Pallesen; Pascal Hommen; Georg L Goebel; Francesco Bosica; Yang Liu; Gavin O'Mahony; Peng Wu

doi:10.1021/acsmedchemlett.3c00341

N-Biphenyl Pyrrolinones and Dibenzofurans as RNA-Binding Protein LIN28 Inhibitors Disrupting the LIN28- Let-7 Interaction

ACS Med Chem Lett. 2023 Nov 14;14(12):1707-1715. doi: 10.1021/acsmedchemlett.3c00341. eCollection 2023 Dec 14.

Authors

Lydia Borgelt^{1

2

3}, Lisa Hohnen^{1

2

4}, Jakob S Pallesen⁵, Pascal Hommen^{1

2

3}, Georg L Goebel^{1

2

3}, Francesco Bosica⁵, Yang Liu^{1

2

3}, Gavin O'Mahony⁵, Peng Wu^{1

2}

Affiliations

¹ Chemical Genomics Centre, Max Planck Institute of Molecular Physiology, Otto-Hahn Str. 15, Dortmund 44227, Germany.
² Department of Chemical Biology, Max Planck Institute of Molecular Physiology, Otto-Hahn Str. 11, Dortmund 44227, Germany.
³ Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn Str. 6, Dortmund 44227, Germany.
⁴ Faculty of Chemistry and Biochemistry, Ruhr-University Bochum, Universitätsstr. 150, Bochum 44801, Germany.
⁵ Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, SE-431 83 Mölndal, Sweden.

Abstract

The RNA-binding protein LIN28 is a regulator of miRNA let-7 biogenesis. Inhibitors of LIN28 are highly sought after given the central role that LIN28 plays in tumorigenesis and development of cancer stem cells as well as LIN28's association with poor clinical prognosis. Although LIN28 inhibitors of different scaffolds have been reported, the potential of most LIN28 inhibiting small molecules was not fully explored since very limited structure-activity relationship (SAR) studies have been performed. We previously identified trisubstituted pyrrolinones as a new class of LIN28 inhibitors disrupting the LIN28-let-7 interaction. Here, we performed extensive SAR by evaluating 95 small molecules and identified new trisubstituted pyrrolinones featuring either an N-biphenyl or N-dibenzofuran substituent, overthrowing the existing conclusion that a salicylic acid moiety is indispensable for activity. Exchange of the negatively charged salicylic acid moiety in LIN28 inhibitors with a heterocyclic substituent is beneficial for membrane permeability, leading to increased activity in a cellular assay, and will potentially reduce toxicity.