1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors.
Aymeric DolboisRajiv K BediElena BochenkovaAnna MüllerElena V Moroz-OmoriDanzhi HuangAmedeo CaflischPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- energy transfer
- prostate cancer
- acute myeloid leukemia
- type diabetes
- quantum dots
- induced apoptosis
- protein protein
- papillary thyroid
- sars cov
- social media
- radical prostatectomy
- amino acid
- molecular docking
- cardiovascular disease
- binding protein
- cell cycle arrest
- high throughput
- small molecule
- nucleic acid
- insulin resistance
- endoplasmic reticulum stress
- oxidative stress
- squamous cell carcinoma
- molecular dynamics simulations
- signaling pathway
- structure activity relationship
- fluorescent probe