SKLB03220

SKLB03220 is a covalent inhibitor of the histone-lysine methyltransferase enhancer of zeste homolog 2 (EZH2; IC₅₀ = 1.72 nM).¹ It also inhibits EZH2^A677G, EZH2^Y641N, and EZH2^Y641F, mutations found in various cancers, when used at a concentration of 10 nM. SKLB03220 is selective for EZH2 over a variety of other histone-lysine methyltransferases, including G9a, SUV39H1, SET domain-containing protein 8 (SETD8), SMYD2, and protein arginine methyltransferase 1-7 (PRMT1-7) at 10 µM but does inhibit EZH1 at 1 and 10 µM. It is also selective for EZH2 over a panel of 224 kinases at 200 nM. SKLB03220 inhibits the proliferation of PA-1 and A2780 ovarian cancer cells in a concentration-dependent manner. It reduces levels of trimethylated histone H3 lysine 27 (H3K27Me3) and induces apoptosis in PA-1 cells. SKLB03220 (75 and 150 mg/kg twice per day) reduces tumor growth in a PA-1 mouse xenograft model.

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1. Zhang, Q., Chen, X., Cao, J., et al. Discovery of a novel covalent EZH2 inhibitor based on tazemetostat scaffold for the treatment of ovarian cancer. J. Med. Chem. 66(3), 1725-1741 (2023).