A-366 is a Potent Histone Methyltransferase G9a Inhibitor

Epigenetic alterations to the genome take place via modifications to the DNA or histones. Meanwhile, those modifications lead to changes in gene expression. Generally, histone lysine methylation is a prominent kind of epigenetic regulation for change of the structure chromatin and gene expression. HMTs have recently generated increasing interest in its therapeutic value in human disease.

G9a and G9a-like protein are HMTs. They can catalyze the mono- and di-methylation of lysine 9 on histone 3 (H3K9me1/2). In a body of literature, the potential link of G9a to a variety of cancers

G9a has a potential link to many cancers, such as leukemias, prostate cancer, hepatocellular carcinoma, and lung cancer.

In this article, we will introduce a potent histone methyltransferase G9a inhibitor A-366 with an IC50 of 3.3 nM in vitro and in vivo.

A 366 is a Potent Histone Methyltransferase G9a Inhibitor 2020 01 23 - A-366 is a Potent Histone Methyltransferase G9a Inhibitor

Firstly, in myelocytic leukemia (AML) cell line MV4;11, A-366 can result in differentiation of this tumor cell line as a dose-dependent manner.

In long-term treatment, A-366 also inhibits proliferation and viability by CD11b staining observation. Whatmore, this compound results in a dose-dependent transition towards sub G1/G0 content consistent with the CD11b staining result.

In the short term observation, A-366 can produce similar but less dramatic effects. A-366 also affects cell morphologication, it increases cytoplasm: nucleus ratio and nuclear lobulation ( indicative of differentiation).

In vivo, in SCID/bg mice with MV4;11 cells, the volume of the tumor reaches ~200 mm3. A-366 treatment to mice at 30 mg/kg/day by osmotic mini-pump for 14 days exhibits no toxicity. In this experiment, A-366 results in a modest 45% tumor growth inhibition. Finally, A-366 exerts a slow but steady decrease in total H3K9me2 levels.

In summary, A-366 can selectively inhibit G9a without affect other histone methyltransferases.

A-366 exhibits lightened cytotoxic effects on cancer cells. Besides, A-366 plays an important role in remaining the G9a/GLP in leukemia. Furthermore, in the mouse model, A-366 significantly results in tumor growth inhibition.


Pappano WN, et al. PLoS One. 2015 Jul 6;10(7):e0131716.