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

Abstract

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. Interestingly, compound and its derivative showed an inhibitory activity against PRMT4 in the micromolar range. Crystal structures showed that compound binds to the PRMT4 active site, displacing strongly the-adenosyl-l-methionine cofactor, occupying its binding site, and interacting with the arginine substrate site through the cytosine moiety that probes the space filled by a substrate peptide methylation intermediate. Furthermore, the binding of the compounds induces important structural switches. These findings open new routes for the conception of new potent PRMT4 inhibitors based on the 5-methylcytosine-adenosine scaffold.This article is part of a discussion meeting issue 'Frontiers in epigenetic chemical biology'.

PRMT6 Promotes Lung Tumor Progression via the Alternate Activation of Tumor-Associated Macrophages

“…Increased expression of PRMT isoforms, for example, PRMT1, CARM1, PRMT5, PRMT6, and PRMT9, in several tumor types has been correlated with poor overall survival (6)(7)(8)(9)(10)(11). In recent years, several small-molecule compounds and peptide inhibitors that target the catalytic/substrate binding domains of PRMTs have been developed and tested (12)(13)(14). However, because some PRMT isoforms display very limited substrate specificity, the development of catalytic inhibitors of PRMTs should not be the sole approach to treat cancers.…”

Structural and biochemical evaluation of bisubstrate inhibitors of protein arginine N-methyltransferases PRMT1 and CARM1 (PRMT4)

“…This degree of selectivity provides a promising framework for the development of higher potency chemical probes for cellular assays. Interestingly, nine structures have recently been added to the PDB of CARM1 from Mus musculus in complex with different aromatic-containing bisubstrate inhibitors (PDB codes 5TBJ, 5TBI, 5TBH, 5LV3, 5LV2 [36] and 5ISB 5IS9, 6DVR and 6D2L [38]). Superposition of these structures with the CARM1-9 complex structure (Supplementary Figure S9) revealed reasonably good overlap of 9's aminopyridine group with the aromatic groups of these inhibitors, particularly in the SAM carboxylate binding pocket (i.e.…”

“…Alternatively, inhibitors may occupy both the SAM and arginine binding sites ( Figure 1B) [28,[33][34][35]. A number of such inhibitors that target CARM1 feature amino adenosine linked to modified cytosine moieties that occupy the SAM and arginine binding site, respectively [36]. The most potent of these inhibitors displayed an IC 50 of 1.5 mM against CARM1, and was 100-fold less potent against PRMT1.…”

The Roles of Host 5-Methylcytosine RNA Methyltransferases during Viral Infections

“…Halby et al developed a convergent synthetic pathway, starting from a protected bromomethylcytosine derivative, to synthesize transition state analogs of DNA methyltransferases [114]. However, they found low activity of seven 5-methylcytosine-adenosine compounds against hDNMT1, hDNMT3Acat, TRDMT1, and other human and viral RNA methyltransferases.…”