Structure-Based Design of inhibitors of the m6A‑RNA writer enzyme METTL3

TitleStructure-Based Design of inhibitors of the m6A‑RNA writer enzyme METTL3
Publication TypeJournal Article
Year of Publication2023
AuthorsBedi R.K, Huang D., Li Y., Caflisch A.
JournalACS Bio & Med Chem Au
Volume3
Issue4
Pagination359–370
Date Published2023 May 03
Type of ArticleResearch Article
Keywordscomputer-aided drug design (CADD), epitranscriptomics, m6A‑RNA, METTL3/METTL14, molecular dynamics, SAR
Abstract

Methyltransferase-like 3 (METTL3) and METTL14 form a heterodimeric complex that catalyzes the most abundant internal mRNA modification, N6-methyladenosine (m6A). METTL3 is the catalytic subunit that binds the co-substrate S-adenosyl methionine (SAM), while METTL14 is involved in mRNA binding. The m6A modification provides post-transcriptional level control over gene expression as it affects almost all stages of the mRNA life cycle, including splicing, nuclear export, translation, and decay. There is increasing evidence for an oncogenic role of METTL3 in acute myeloid leukemia. Here, we use structural and dynamic details of the catalytic subunit METTL3 for developing small-molecule inhibitors that compete with SAM. Starting from a hit identified by high-throughput docking, protein crystallography and molecular dynamics simulations were employed to guide the optimization of inhibitory activity. The potency was successfully improved by 8000-fold as measured by a homogeneous time-resolved fluorescence assay. The optimized compound is selective against the off-targets RNA methyltransferases METTL1 and METTL16.

DOI10.1021/acsbiomedchemau.3c00023
pubindex

0287

Alternate JournalACS Bio. Med. Chem. Au
Highlight Role: 
Drug Design