CM-272

CM-272 is a reversible inhibitor of the histone methyltransferases G9a and GLP, as well as DNA methyltransferase 1 (DNMT1), DNMT3A, and DNMT3B (IC₅₀s = 8, 2, 382, 85, and 1,200 nM, respectively).¹ It inhibits the growth of, and induces apoptosis in, CEMO-1, MV4-11, and OCI-LY10 cancer cells (GI₅₀s = 218, 269, and 455 nM, respectively). It also induces the expression of IFN-stimulated genes, as well as increases the expression of calreticulin and secretion of high-mobility group protein B1 (HMGB1), markers of immunogenic cell death, in the same cells. CM-272 (2.5 mg/kg) reduces tumor growth in MV4-11 acute myeloid leukemia (AML) and EGI-1 cholangiocarcinoma mouse xenograft models.^2,3 It increases survival in CEMO-1 acute lymphocytic leukemia (ALL) and RT112 bladder cancer mouse xenograft models when administered at doses of 2.5 and 5 mg/kg, respectively.^1,4

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1. San José-Enériz, E., Agirre, X., Rabal, O., et al. Discovery of first-in-class reversible dual small molecule inhibitors against G9a and DNMTs in hematological malignancies. Nat. Commun. 8, 15424 (2017).

2. Rabal, O., San José-Enériz, E., Agirre, X., et al. Discovery of reversible DNA methyltransferase and lysine methyltransferase G9a inhibitors with antitumoral in vivo efficacy. J. Med. Chem. 61(15), 6518-6545 (2018).

3. Colyn, L., Bárcena-Varela, M., Álvarez-Sola, G., et al. Dual targeting of G9a and DNMT1 for the treatment of experimental cholangiocarcinoma. Hepatology (2020).

4. Segovia, C., San José-Enériz, E., Munera-Maravilla, E., et al. Inhibition of a G9a/DNMT network triggers immune-mediated bladder cancer regression. Nat. Med. 25(7), 1073-1081 (2019).