Abstract 3265: Discovery of a first-in-class reversible DNMT1-selective inhibitor

Abstract

Abstract DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A, and DNMT3B through irreversible covalent interactions. These agents induce significant toxicity to normal blood cells thus limiting their clinical doses. We report the discovery of a series of potent first-in-class DNMT1-selective inhibitors that compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA. These compounds induce robust loss of DNA methylation, transcriptional activation, and cancer cell growth inhibition in vitro leading to superior tumor regression and survival in mouse models of acute myeloid leukemia due to improved in vivo tolerability compared with decitabine. Citation Format: Melissa B. Pappalardi. Discovery of a first-in-class reversible DNMT1-selective inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3265.