Synthesis and evaluation of RNase L-binding 2-aminothiophenes as anticancer agents.

Aminothiophene is a scaffold that is widely present in drugs and biologically active small molecules as chemical probes. In this study, 43 compounds sharing a 2-aminothiophenone-3-carboxylate (ATPC) scaffold, known to activate the ribonuclease L (RNase L), were synthesized and selected ATPCs showed enhancement of thermal stability of RNase L upon binding. Screening of antiproliferation activities against human cancer cell lines revealed that ATPCs represented by compounds 4l and 50 showed potent single-digit micromolar antiproliferation activity against human cancer cell lines. Compounds 4l and 50 exhibited time- and dose-dependent proliferation inhibition, induced cellular apoptosis measured by cleaved PARP and via flow cytometry, inhibited cell migration, and inhibited cell colony formation. Combining the results reported in this work, ATPCs were evaluated as potential anticancer agents mediated by RNase L-binding and apoptosis induction. The work contributes to the study on the polypharmacological properties of aminothiophene-containing small molecules.

Aminothiazolone Inhibitors Disrupt the Protein-RNA Interaction of METTL16 and Modulate the m6A RNA Modification.

Targeting RNA-binding and modifying proteins via small molecules to modulate post-transcriptional modifications have emerged as a new frontier for chemical biology and therapeutic research. One such RNA-binding protein that regulates the most prevalent eukaryotic RNA modification, N6-methyladenosine (m6A), is the methyltransferase-like protein 16 (METTL16), which plays an oncogenic role in cancers by cofunctioning with other nucleic acid-binding proteins. To date, no potent small-molecule inhibitor of METTL16 or modulator interfering with the METTL16-RNA interaction has been reported and validated, highlighting the unmet need to develop such small molecules to investigate the METTL16-involved regulatory network. Herein, we described the identification of a series of first-in-class aminothiazolone METTL16 inhibitors via a discovery pipeline that started with a fluorescence-polarization (FP)-based screening. Structural optimization of the initial hit yielded inhibitors, such as compound 45, that showed potent single-digit micromolar inhibition activity against the METTL16-RNA binding. The identified aminothiazolone inhibitors can be useful probes to elucidate the biological function of METTL16 upon perturbation and evaluate the therapeutic potential of METTL16 inhibition via small molecules at the post-transcriptional level.