Nucleoside and Non-Nucleoside DNA Methyltransferase 1 Inhibitors in Epigenetic and Combination Therapies in Cancer: A Scoping Review

Abstract

DNA methylation is an epigenetic mechanism of gene silencing crucial to the regulation of gene expression in normal physiological events such as differentiation and X-inactivation. However, aberrant silencing of regulatory genes can contribute to oncogenic transformation, further perpetuated due to the heritability of these changes down the cell line. Though aberrant DNA methylation is implicated across cancer types, epigenetic therapy with DNA methyltransferase 1 (DNMT1) depleting drugs is only approved in the treatment of hematological cancers. This limitation is due to the drugs’ high toxicity, a byproduct of their mechanism as nucleoside analogs. Identifying less toxic nucleoside analogs or developing non-nucleoside analogs is necessary to expand the application of epigenetic therapy. This review examines the existing nucleoside and non-nucleoside DNMT1-inhibitors at various stages of preclinical and clinical development, and overviews prospective applications of epigenetic therapy in solid tumors as monotherapy and combined therapy. The list of drugs reported in this review is non-comprehensive as it excludes primary research on drugs last tested prior to the FDA approval of azacitidine and drugs not tested or inviable in human cells. This is to limit the survey to studies that intend to improve upon the pharmacological profile of the approved drugs. Of particular importance are the recently developed DNMT1-inhibitor (DNMT1-i) GSK analogs and the advancements in protein modeling that have elucidated their mechanism to the greatest precision yet. Not yet discussed in length in secondary literature, these findings provide a clearer model for the development of more specific DNMT-is. Furthermore, evidence showing enhanced efficacy of DNMT1 inhibitors when combined with DNA damaging agents identifies epigenetic combination therapy as a pertinent focus of future research.