1,4,9-Triazaspiro[5.5]undecan-2-one derivatives as potent and selective METTL3 inhibitors

Title1,4,9-Triazaspiro[5.5]undecan-2-one derivatives as potent and selective METTL3 inhibitors
Publication TypeJournal Article
Year of Publication2021
AuthorsDolbois A., Bedi R.K, Bochenkova E., Müller A., Moroz-Omori E.V, Huang D., Caflisch A.
JournalJournal of Medicinal Chemistry
Date Published2021 Aug 25
Type of ArticleResearch 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.



Alternate JournalJ. Med. Chem.
PubMed ID34431664