Identification and characterization of PKF118-310 as a KDM4A inhibitor

Abstract

Epigenetic modifications are functionally involved in gene expression regulation. In particular, histone posttranslational modifications play a crucial role in functional chromatin organization. Several drugs able to inhibit or stimulate some families of proteins involved in epigenetic histone regulation have been found, a number of which are FDA-approved for the treatment of cutaneous T-cell lymphoma or are in phase I/II/III clinical trials for solid tumors. Although some protein families, such as histone deacetylases and their inhibitors, are well characterized, our understanding of histone lysine demethylases is still incomplete. We describe the in silico, in vitro, and cell-based characterization of the compound PKF118-310, an antagonist of transcription factor 4 (TCF4)/β-catenin signaling, as inhibitor of KDM4A. PKF118-310 potential inhibitor activity was discovered via virtual screening on the crystal structure of KDM4A. A peptide-based histone trimethylation assay developed in-house confirmed its potent KDM4A inhibitor activity. Its protein target was identified by cellular thermal shift assay experiments. PKF118-310 anticancer activity was observed in both liquid and solid tumor cells, and shown to have a dose- and time-dependent effect. We demonstrate the previously unreported inhibitory action of PKF118-310 on KDM4A. Our findings open up the possibility of developing the first KDM4A-specific inhibitors and derivatives.

The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery

“…On the one hand, pathological tissues and cells exhibit epigenetic imprints of the developmental or differentiation stages from which they originate and, on the other hand, they acquire disease-specific epigenetic alterations. Exciting outcomes of these comparisons are the identification of disease-specific regulators and distant enhancers regulating oncogenes, the functional characterization of mutated/aberrantly expressed chromatin and transcriptional regulators, and how these might be profitably targeted by novel (Franci, Sarno et al 2016) as well as existing therapies (Angela, Carafa et al 2016, Chun, Lim et al 2016, Martens 2016). …”

Toxoflavin Produced by Burkholderia gladioli from Lycoris aurea Is a New Broad-Spectrum Fungicide

“…In addition to its antimicrobial potential, it has been shown that toxoflavin acts as a small molecule inhibitor of signaling pathways and targets involved in cancer development and treatment (24,(40)(41)(42). It was also suggested as a potential promising chemotherapeutic drug candidate for different cancers (22,24,43,44).…”

“…In addition to its antimicrobial potential, it has been shown that toxoflavin acts as a small molecule inhibitor of signaling pathways and targets involved in cancer development and treatment (24,(40)(41)(42). It was also suggested as a potential promising chemotherapeutic drug candidate for different cancers (22,24,43,44). Although the clinical development of toxoflavin might be limited by its potential toxicity (19), a number of toxoflavin analogues have been prepared due to their effective biological activity and extensive use (21,45).…”

“…Finally, as expected, we found that Burkholderia gladioli HDXY-02 isolated from L. aurea has strong antagonistic activities against all tested fungal pathogens. The antibiotic produced by HDXY-02 that contributes to its antifungal activity was toxoflavin (PKF118-310), which possesses the pyrimido [5,4-e] [1,2,4]triazine ring (also known as xanthothricin) and has considerable antibiotic activity (19)(20)(21) and antitumor properties (22)(23)(24). More importantly, the result showed that purified toxoflavin from B. gladioli HDXY-02 fermentation broth has a remarkable antifungal activity against all tested species, including azole drug-susceptible and -resistant A. fumigatus species.…”

MiR‐10a functions as a tumor suppressor in prostate cancer via targeting KDM4A

“…10 KDM4A relies on its demethylase activity to promote the removal of the repressive H3K9me3 mark and that of H3K36me3, a mark linked to transcriptional elongation. 12 Aberrant expression of KDM4A was observed in a variety of cancer types. 12 Aberrant expression of KDM4A was observed in a variety of cancer types.…”