A. Dolbois; R.K. Bedi; E. Bochenkova; A. Müller; E.V. Moroz-Omori; D. Huang; A. Caflisch

Journal: J. Med. Chem.
Year: 2021
Volume: 64
Issue: 17
Pages: 12738-12760
DOI: 10.1021/acs.jmedchem.1c00773
Type of Publication: Journal Article


N6-methyladenosine (m6A) is the most frequent of the 160 RNA modifications reported so far. Accumulating evidence suggests that the METTL3/METTL14 protein complex, part of the m6A regulation machinery, is a key player in a variety of diseases including several types of cancer, type 2 diabetes, and viral infections. Here we report on a protein crystallography-based medicinal chemistry optimization of a METTL3 hit compound that has resulted in a 1400-fold potency improvement (IC50 of 5 nM for the lead compound 22 (UZH2) in a time-resolved Förster resonance energy transfer (TR-FRET) assay). The series has favorable ADME properties as physicochemical characteristics were taken into account during hit optimization. UZH2 shows target engagement in cells and is able to reduce the m6A/A level of polyadenylated RNA in MOLM-13 (acute myeloid leukemia) and PC-3 (prostate cancer) cell lines.