JNJ-1661010

M⁶A modification in transcriptome is critical in regulating different cellular processes, including cancer. In human beings, METTL3 is the major m⁶A writer that works in association with METTL14, an accessory protein. Extensive study revealed that cancer progression for acute myeloid leukemia, gastric cancer, colorectal cancer, hepatocellular carcinoma, and lung cancer is directly contributed by irregular expression of METTL3.

Targeting METTL3 has opened a new window in the development of novel inhibitors/drugs.

In this study, commercially available natural compounds were randomly screened to avoid the bias of screening small molecules on the basis of structural similarity. From 810 compounds that were screened, 80 commercially available compounds were showing better score when compared with the existing substrate/substrate-analogue and the inhibitor bound crystal structures in terms of docking score and binding energy calculation.

Among this pool of compounds, the best seven small molecules have been selected and further validated by different computational tools like binding energy calculation, molecular dynamics simulation, ADME analysis, and toxicity prediction. The novel hits found in this study can function as lead compounds which can be developed into inhibitors as well as drugs, specific against METTL3.

Gnaphalium polycaulon commonly known as "cudweed" has been used throughout South America as an infusion to treat colds, bronchitis, fever or pneumonia.

This study aimed to determine the antibacterial and anti-inflammatory activities of the aqueous extract of Gnaphalium polycaulon and identify the related compounds.

A bio-guided isolation of the active compounds of Gnaphalium polycaulon was carried out, selecting the fractions depending on their antibacterial, anti-inflammatory and cytotoxic activities. The antibacterial effect was studied against Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pneumoniae; and the anti-inflammatory study was performed by measuring the inhibition of NF-κB in BEAS-2B and IMR-90 cell cultures.

Three compounds were obtained and characterised by nuclear magnetic resonance and mass spectrometry. These compounds are 2-(4-(1-H-tetrazol-1-yl) phenyl)-2-aminopropanoic acid (1), N-phenyl-4-(3-phenyl-1,2,4-thiadiazol-5-yl) piperazine-1-carboxamide (2) and N-(4-ethoxyphenyl)-4-(2-methylimidazo-[1,2-α] pyridine-3-yl) thiazol-2-amine (3). All compounds showed antibacterial activity with MIC values of 44.80-44.85, 0.017-0.021 and 0.0077-0.0079 μM, respectively, in the Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus and Streptococcus pneumoniae strains, while the positive control, Ofloxacin, had a MIC value of 27.64-27.67 μM. This was corroborated through a zone inhibition assay, where compound 3 (11.36-11.67 mm) was much more active than the positive control (Ofloxacin, 23.41-24.12 mm), while compounds 2 (26.47-27.64 mm) and 1 (28.39-29.76 mm) displayed similar antibacterial potential to the positive control. Finally, all the compounds presented NF-κB inhibitory activity, compounds 3 (IC₅₀ = 0.0071-0.0073 μM) and 2 (IC₅₀ = 0.016-0.019 μM) being the most promising. Compound 1 (IC₅₀ = 44.24-44.26 μM) had less anti-inflammatory potential, being also the closest to the values displayed by the positive control (Celastrol, IC₅₀ = 7.41 μM).

In the present study, three compounds were isolated for the first time from the aqueous extract of Gnaphalium polycaulon. Their antibacterial and anti-inflammatory potential was tested and showcased.