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

ABSTRACT

Introduction: DNA methyltransferases (DNMTs), important enzymes involved in epigenetic regulation of gene expression, represent promising targets in cancer therapy. DNMT inhibitors (DNMTi), which can modulate the aberrant DNA methylation pattern in a reversible way via inhibiting DNMT activity, have attracted significant attention in recent years.

Areas covered: This review outlines the newly patented inhibitors targeting DNMTs, mainly incorporating small molecular inhibitors and oligonucleotide derivatives. The chemical structures, biological activity, and the encouraging clinical research in progress are delineated in detail.

Expert opinion: 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.

KEYWORDS:

• DNMT inhibitors (DNMTi)
• epigenetic therapy
• nucleotide derivatives
• drug combination
• allosteric inhibitor

Article highlights

• This article covers the recent patent literatures on DNMT inhibitors, including small molecular inhibitors and oligonucleotide derivatives.

• Chemical structures, biological activity and inhibition mechanism of representative inhibitors are summarized and provided in detail.

• The strategy combining DNMTi and other drugs, such as HDACi, has gained widespread appeal in clinical investigation of cancer therapeutics. Specifically, DNMTi in conjuction with immunotherapy has been increasingly concerned in recent years.

• Feasible strategies for designing potent and selective DNMTi are comprehensively discussed. The deep understanding of the DNMT structures and enriched chemical space targeting DNMTs would shed new light on DNMTi design in the near future.

This box summarizes key points contained in the article.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This work was supported by the National Basic Research Program (2015CB910304 to C Luo), the National Natural Science Foundation of China (21472208 to C Luo and 81302700 to Z Liang), Fund of State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science (TMC201505 to C Luo).