Aberrant DNA hypermethylation within gene promoter regions and subsequent gene silencing are near universal hallmarks of human cancer. Upon DNA replication, these methylation profiles are copied onto the newly synthesized DNA strand by DNA methyltransferase 1 (DNMT1), ensuring heritability of the epigenetic profile upon cell division. Reversal of DNA methyl marks by a hypomethylating agent such as decitabine, delivers clinical benefit for the treatment of cancers such as acute myeloid leukemia. These agents have considerable drawbacks limiting their potential therapeutic benefit, including IV administration, poor PK properties, lack of selectivity and a mechanism that requires incorporation into replicating DNA. This indirect, irreversible inhibition of the entire DNMT family (DNMT1, 3a and 3b), and subsequent DNA damage, induces significant dose-limiting toxicity, preventing sufficient target engagement required for maximal demethylation and limiting therapeutic utility. As a result, the past few decades have seen considerable interest in the pursuit of potent, selective DNMT1 inhibitors. However, these attempts have been fraught with difficulty and have delivered little, if any, success. Here we report the outcome of a high-throughput screen and the development of a robust screening cascade to identify a series of molecules that were found to be non-DNA incorporating and highly selective for DNMT1 over DNMT3a or DNMT3b. Structure-activity relationship (SAR) optimization led to the discovery of potent tool compounds that induced robust decreases in global DNA methylation in cancer cells, induced transcriptional activation of many silenced genes, and inhibited cancer cell growth. Rodent in vivo studies with these agents demonstrated appreciable exposure, decreased DNA methylation and a dose-dependent decrease in tumor growth with regression at well-tolerated doses.

Discovery of a selective, non-nucleoside small molecule inhibitor of DNA methyltransferase 1 (DNMT1)

256th National Meeting (2018)

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