| Structural highlights
Function
MET14_HUMAN N6-methyltransferase that methylates adenosine residues of some mRNAs and acts as a regulator of the circadian clock and differentiation of embryonic stem cells. N6-methyladenosine (m6A), which takes place at the 5'-[AG]GAC-3' consensus sites of some mRNAs, plays a role in the efficiency of mRNA splicing, processing and mRNA stability (PubMed:24316715, PubMed:24407421, PubMed:25719671). M6A regulates the length of the circadian clock: acts as a early pace-setter in the circadian loop. M6A also acts as a regulator of mRNA stability: in embryonic stem cells (ESCs), m6A methylation of mRNAs encoding key naive pluripotency-promoting transcripts results in transcript destabilization (By similarity).[UniProtKB:Q3UIK4][1] [2] [3]
Publication Abstract from PubMed
N(6)-methyladenosine (m(6)A) is the most frequent of the 160 RNA modifications reported so far. Accumulating evidence suggests that the METTL3/METTL14 protein complex, part of the m(6)A 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(50) of 5 nM for the lead compound 22 (UZH2) in a time-resolved Forster 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 m(6)A/A level of polyadenylated RNA in MOLM-13 (acute myeloid leukemia) and PC-3 (prostate cancer) cell lines.
1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors.,Dolbois A, Bedi RK, Bochenkova E, Muller A, Moroz-Omori EV, Huang D, Caflisch A J Med Chem. 2021 Sep 9;64(17):12738-12760. doi: 10.1021/acs.jmedchem.1c00773. , Epub 2021 Aug 25. PMID:34431664[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, Jia G, Yu M, Lu Z, Deng X, Dai Q, Chen W, He C. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014 Feb;10(2):93-5. doi: 10.1038/nchembio.1432. Epub 2013 Dec 6. PMID:24316715 doi:http://dx.doi.org/10.1038/nchembio.1432
- ↑ Ping XL, Sun BF, Wang L, Xiao W, Yang X, Wang WJ, Adhikari S, Shi Y, Lv Y, Chen YS, Zhao X, Li A, Yang Y, Dahal U, Lou XM, Liu X, Huang J, Yuan WP, Zhu XF, Cheng T, Zhao YL, Wang X, Rendtlew Danielsen JM, Liu F, Yang YG. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014 Feb;24(2):177-89. doi: 10.1038/cr.2014.3. Epub 2014 Jan 10. PMID:24407421 doi:http://dx.doi.org/10.1038/cr.2014.3
- ↑ Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015 Feb 26;518(7540):560-4. doi: 10.1038/nature14234. PMID:25719671 doi:http://dx.doi.org/10.1038/nature14234
- ↑ Dolbois A, Bedi RK, Bochenkova E, Müller A, Moroz-Omori EV, Huang D, Caflisch A. 1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors. J Med Chem. 2021 Sep 9;64(17):12738-12760. PMID:34431664 doi:10.1021/acs.jmedchem.1c00773
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