GSK3685032

GSK3685032 is an inhibitor of DNA methyltransferase 1 (DMNT1; IC₅₀ = 0.23 µM).¹ It is selective for DMNT1 over DMNT3A/3L and DMNT3B/3L and a panel of 34 methyltransferases and 369 kinases (IC₅₀s = >10 µM for all). GSK3685032 inhibits the proliferation of 51 hematological cancer cell lines (median IC₅₀ = 0.64 µM). It decreases overall DNA methylation and gene expression in MV4-11, THP-1, and NOMO-1 acute myeloid leukemia (AML) cells in a time- and concentration-dependent manner. GSK3685032 increases the expression of the genes encoding chemokine (C-X-C) motif ligand 11 (CXCL11), IFN-α-inducible protein 27 (IFI27), and melanoma-associated antigen 4 (MAGEA4). In vivo, GSK3685032 (45, 30, or 15 mg/kg twice per day) reduces tumor volume and increases survival but does decrease blood numbers of neutrophils and red blood cells in SKM-1 and MV4-11 leukemia mouse xenograft models.

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1. Pappalardi, M.B., Keenan, K., Cockerill, M., et al. Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia. Nat. Cancer 2(10), 1002-1017 (2021).