Hijacking DNA methyltransferase transition state analogues to produce chemical scaffolds for PRMT inhibitors.

DNA, RNA and histone methylation is implicated in various human diseases such as cancer or viral infections, playing a major role in cell process regulation, especially in modulation of gene expression. Here we developed a convergent synthetic pathway starting from a protected bromomethylcytosine derivative to synthesize transition state analogues of the DNA methyltransferases. This approach led to seven 5-methylcytosine-adenosine compounds that were, surprisingly, inactive against hDNMT1, hDNMT3Acat, TRDMT1 and other RNA human and viral methyltransferases.

Disruptor of telomeric silencing 1-like (DOT1L): disclosing a new class of non-nucleoside inhibitors by means of ligand-based and structure-based approaches.

Chemical inhibition of chromatin-mediated signaling involved proteins is an established strategy to drive expression networks and alter disease progression. Protein methyltransferases are among the most studied proteins in epigenetics and, in particular, disruptor of telomeric silencing 1-like (DOT1L) lysine methyltransferase plays a key role in MLL-rearranged acute leukemia Selective inhibition of DOT1L is an established attractive strategy to breakdown aberrant H3K79 methylation and thus overexpression of leukemia genes, and leukemogenesis. Although numerous DOT1L inhibitors have been several structural data published no pronounced computational efforts have been yet reported.

Identification of epigenetic factors regulating the mesenchyme to epithelium transition by RNA interference screening in breast cancer cells.

Background: In breast cancer, the epithelial to mesenchyme transition (EMT) is associated to tumour dissemination, drug resistance and high relapse risks. It is partly controlled by epigenetic modifications such as histone acetylation and methylation. The identification of genes involved in these reversible modifications represents an interesting therapeutic strategy to fight metastatic disease by inducing mesenchymal cell differentiation to an epithelial phenotype.

Antimalarial potential of xestoquinone, a protein kinase inhibitor isolated from a Vanuatu marine sponge Xestospongia sp.

As part of our search for new antimalarial drugs, we have screened for inhibitors of Pfnek-1, a protein kinase of Plasmodium falciparum, in south Pacific marine sponges. On the basis of a preliminary screening, the ethanolic crude extract of a new species of Xestospongia collected in Vanuatu was selected for its promising activity. A bioassay-guided fractionation led us to isolate xestoquinone which inhibits Pfnek-1 with an IC(50) around 1 microM.

Acylphloroglucinol derivatives from Mahurea palustris.

Five new acylphloroglucinol derivatives, mahureones A-E (1, 3-6), have been isolated from the leaves of Mahurea palustris, and their structures determined by spectroscopic means. During the isolation process, several byproducts (7-9) were formed by reaction of one of the isoprenyl side chains with TFA, water, and acetonitrile. All the compounds were assayed for their ability to inhibit human DNA polymerase beta.

A novel synthetic inhibitor of CDC25 phosphatases: BN82002.

CDC25 dual-specificity phosphatases are essential regulators that dephosphorylate and activate cyclin-dependent kinase/cyclin complexes at key transitions of the cell cycle. CDC25 activity is currently considered to be an interesting target for the development of new antiproliferative agents. Here we report the identification of a new CDC25 inhibitor and the characterization of its effects at the molecular and cellular levels, and in animal models.

Inhibitors of the CDC25 phosphatases.

As essential cell cycle regulators, the CDC25 phosphatases are currently considered as potential targets for the development of novel therapeutic approaches. Here, we review the function and regulation of CDC25 phosphatases, their involvement in cancer and Alzheimer's disease, and the properties of several recently identified inhibitors.