Histone Methyltransferase Modulator

UNC10013 is an inhibitor targeting the triple Tudor domain (3TD) of SETDB1. UNC10013 covalently binds to Cys385 of SETDB1 3TD, acts as a negative allosteric modulator of the methyltransferase domain of SETDB1, reduces the level of Akt methylation mediated by SETDB1, and blocks Tyr308 phosphorylation of Akt. UNC10013 is applicable to cancer-related research.

HDAC3-IN-2 (compound 4i) is a pyrazinyl hydrazide-based HDAC3 inhibitor (IC₅₀: 14 nM) that efficiently targets triple-negative breast cancer cells. HDAC3-IN-2 is cytotoxic with an IC₅₀ of 0.55 μM against 4T1 and an IC₅₀ of 0.74 μM against MDA-MB-231. HDAC3-IN-2 has anti-tumor efficacy in vivo in tumor-bearing mouse models, selectively increasing the acetylation levels of H3K9, H3K27 and H4K12, increasing the contents of apoptosis-related caspase-3, caspase-7 and cytochrome c, and reducing Proliferation-related Bcl-2, CD44, EGFR, and Ki-67 levels.

NSD2/H3K36me2 modulator-1 is an orally active NSD2/H3K36me2 modulator. NSD2/H3K36me2 modulator-1 competitively binds to the SAM pocket of NSD2, potently inhibits NSD2 expression and suppresses H3K36me2 methylation. NSD2/H3K36me2 modulator-1 reverses epithelial-mesenchymal transition (EMT), inhibits cell migration, and induces G0/G1 phase arrest and apoptosis. NSD2/H3K36me2 modulator-1 induces decreased Mitochondrial membrane potential (MMP) and subsequent Reactive oxygen species (ROS) generation. NSD2/H3K36me2 modulator-1 can be used to research the NSD2-targeting epigenetic anticancer strategies for hepatocellular carcinoma (HCC).

NT32 is a selective METTL13 stabilizer with a K_d value of 14 μM. NT32 could occupy both the SAM/SAH-binding pocket and the peptide substrate-binding site of METTL13 simultaneously. NT32 specifically targets and stabilizes METTL13. NT32 shows no inhibitory activity against non-small cell lung cancer.