DNA methyltransferase inhibitors: an updated patent review (2012-2015)

Abstract

Two drugs, azacitidine and decitabine, have evidently shown efficacy in hematologic malignancies, yet do not work well on solid tumors, have low specificity, substantial toxicity, and poor bioavailability. With the rapid advancement in systems biology, drug combinations, such as DNMTi, in conjugation with histone deacetylase inhibitors (HDACi) or immunotherapy, probably serve as an efficient way of implementing epigenetic therapy. Meanwhile, the resolved autoinhibitory structures of DNMTs afford a novel strategy for targeting the protein-protein interface involved in the autoinhi-bitory interactions. The molecular mechanism underlying the conformational transitions would also shed new light on the design of allosteric inhibitors. Both strategies would produce inhibitors with more selectivity compared to nucleotide derivatives.

Peperomin E Induces Promoter Hypomethylation of Metastatic-Suppressor Genes and Attenuates Metastasis in Poorly Differentiated Gastric Cancer

“…Several natural products, such as genistein, laccaic acid A, and (-)-epigallocatechin-3-O-gallate (EGCG), were reported to inhibits DNMT activity. Unfortunately, the potency of these compounds is lower than that of the nucleoside analogs and their in vivo inhibitory activity against solid tumors is rarely reported [60][61]. This situation prompts an urgent need to discover new-generation DNMT inhibitors with high in vitro and in vivo potency against tumors.…”

Alterations of Epigenetic Regulators in Pancreatic Cancer and Their Clinical Implications

“…Nucleoside analogs based on epigenetic inhibitors 5-azacytidine and 5-aza-2′-dC are in Phase I-III clinical trials for many human diseases, and two DNMT inhibitors, azacytidine and decitabine, have shown efficacy and received FDA approval for the treatment of myelodysplastic syndrome but not solid tumors [31,32]. Nevertheless, some studies showed 5-aza-2′-dC decreased pancreatic cancer cell proliferation and induced cell cycle arrest in an in vitro model [33,34,35].…”

Clinical significance of promoter hypermethylation of genes in ovarian cancer

“…AZA and DAC have evidently demonstrated efficacy in hematologic malignancies such as MDS, AML and CLL, however, the use of DNMTis in solid tumors seems limited because of the low specificity, substantial toxicity, and poor bioavailability [132]. Moreover, the solid tumors patients also have DNMTis associated toxicity issue.…”