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.

Protein arginine methylation is a common post-translational modification which is crucial for a variety of biological processes. Dysregulation of protein arginine methyltransferases (PRMTs) activity has been implicated in cancer and other serious diseases. Thus, small molecule inhibitors against PRMT have great potential for therapeutic development. Herein, through the combination of virtual screening and bioassays, six small molecular compounds were identified as PRMT1 inhibitors. Amongst them, the binding affinity of compounds DCLX069 and DCLX078 with PRMT1 was further validated by T1ρ and saturation transfer difference (STD) NMR experiments. Most important of all, both compounds effectively blocked cell proliferation in breast cancer, liver cancer and acute myeloid leukemia cell lines. The binding mode analysis from molecular docking simulations theoretically indicated that both inhibitors occupied the SAM binding pocket to exert the inhibitory effect. Taken together, our compounds enriched the structural scaffolds as PRMT1 inhibitors and afforded clues for further optimization.

The receptor tyrosine kinase c-MET displays aberrant activation in the malignant phenotype of various tumors, and thus, has drawn considerable attention as drug target for cancer therapy. Many c-MET inhibitors are now under clinical investment, and one of them - Cabozantinib - has been approved by US FDA in 2012 for the treatment of medullary thyroid cancer, which further proved the feasibility of c-MET inhibition method in cancer therapy. This article briefly outlines the role of c-MET in oncogenesis and provides a broad overview of the assays used to characterize new inhibitors. Then, a series of representative small-molecule inhibitors of c-MET, especially from the published patent literature from 2011 to 2013, are recorded. Herein, the challenges in the kinase inhibitor design, such as the inhibitor selectivity and resistance mutations, are also discussed. Up to now, at least 17 inhibitors of c-MET are under clinical evaluation, and several agents exhibit encouraging results. Thus, inhibiting c-MET signaling has major therapeutic value in cancer therapy. Focus on the selectivity of both types of inhibitors, with potent selectivity or multi-targets, have demonstrated antitumor efficacy. The network pharmacology and clinical trials integrated would provide powerful tools to further evaluate the superiority of both inhibitors in continued efficacy and toxicity.