7O2F

Crystal structure of the human METTL3-METTL14 complex bound to Compound 22 (UZH2)

Summary for 7O2F

• Entry DOI: 10.2210/pdb7o2f/pdb
• Descriptor: N6-adenosine-methyltransferase catalytic subunit, N6-adenosine-methyltransferase non-catalytic subunit, 4-[4-[(4,4-dimethylpiperidin-1-yl)methyl]-2,5-bis(fluoranyl)phenyl]-9-[6-(methylamino)pyrimidin-4-yl]-1,4,9-triazaspiro[5.5]undecan-2-one, ... (5 entities in total)
• Functional Keywords: mettl3, inhibitor, complex, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 62338.00

Authors

Bedi, R.K.,Dolbois, A.,Caflisch, A. (deposition date: 2021-03-30, release date: 2021-09-01, Last modification date: 2024-11-13)

Primary citation

Dolbois, A.,Bedi, R.K.,Bochenkova, E.,Muller, A.,Moroz-Omori, E.V.,Huang, D.,Caflisch, A.
1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors.
J.Med.Chem., 64:12738-12760, 2021

PubMed Abstract: -methyladenosine (mA) is the most frequent of the 160 RNA modifications reported so far. Accumulating evidence suggests that the METTL3/METTL14 protein complex, part of the mA 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 (IC of 5 nM for the lead compound () 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. shows target engagement in cells and is able to reduce the mA/A level of polyadenylated RNA in MOLM-13 (acute myeloid leukemia) and PC-3 (prostate cancer) cell lines.

PubMed: 34431664
DOI: 10.1021/acs.jmedchem.1c00773

Experimental method

X-RAY DIFFRACTION (2.1 Å)