Discovery of a Highly Potent Lysine Methyltransferases G9a/NSD2 Dual Inhibitor to Treat Solid Tumors

Both G9a and NSD2 have been recognized as promising therapeutic
targets for cancer treatment. However, G9a inhibitors only showed
moderate inhibitory activity against solid tumors and NSD2 inhibitors
were limited to the treatment of hematological malignancies. Inspired
by the advantages of dual-target inhibitors that show great potential
in enhancing efficiency, we developed a series of highly potent G9a/NSD2
dual inhibitors to treat solid tumors. The candidate 16 demonstrated much enhanced antiproliferative activity compared to
the selective G9a inhibitor 3 and NSD2 inhibitor 15. In addition, it exhibited superior potency in inhibiting
colony formation, inducing cell apoptosis, and blocking cancer cell
metastasis. Furthermore, it effectively inhibited the catalytic functions
of both G9a and NSD2 in cells and exhibited significant antitumor
efficacy in the PANC-1 xenograft model with good safety. Therefore,
compound 16 as a highly potent G9a/NSD2 dual inhibitor
presents an attractive anticancer drug candidate for the treatment
of solid tumors.