Methyltransferase Inhibitors: Competing with, or Exploiting the Bound Cofactor.

Renato Ferreira De Freitas,Matthieu Schapira,Danton Ivanochko

doi:10.3390/molecules24244492

Abstract

Protein methyltransferases (PMTs) are enzymes involved in epigenetic mechanisms, DNA repair, and other cellular machineries critical to cellular identity and function, and are an important target class in chemical biology and drug discovery. Central to the enzymatic reaction is the transfer of a methyl group from the cofactor S-adenosylmethionine (SAM) to a substrate protein. Here we review how the essentiality of SAM for catalysis is exploited by chemical inhibitors. Occupying the cofactor binding pocket to compete with SAM can be hindered by the hydrophilic nature of this site, but structural studies of compounds now in the clinic revealed that inhibitors could either occupy juxtaposed pockets to overlap minimally, but sufficiently with the bound cofactor, or induce large conformational remodeling leading to a more druggable binding site. Rather than competing with the cofactor, other inhibitors compete with the substrate and rely on bound SAM, either to allosterically stabilize the substrate binding site, or for direct SAM-inhibitor interactions.

Highlights

Protein methyltransferases (PMTs) transfer a methyl group from the cofactor S-adenosylmethionine (SAM) to a substrate protein
A cocrystal structure of the PRMT1-substrate inhibitors to bind theirvia target (SAH)-GSK3368715 complex demonstrated that the methylamino group of GSK3368715 projects through the substrate arginine site towards the sulfur and tri-methylated E72 and found that this slow methylation activity led to an improved IC50 value when compared to the inhibitory effect of the original BIX-01294 molecule [81]
Enzyme assays demonstrated that MRK-740 is a substrate-competitive, SAM-uncompetitive inhibitor, and a cocrystal structure of the PR-domain of PRDM9 in a ternary complex with SAM and MRK-740 revealed that MRK-740 makes multiple interactions with SAM and PRDM9 driven by aromatic and hydrophobic substituents on the inhibitor (Figure 9G)

Summary

Introduction

Protein methyltransferases (PMTs) transfer a methyl group from the cofactor S-adenosylmethionine (SAM) to a substrate protein. Most PMT inhibitors directly compete with either the cofactor or the substrate, each occupying. Most PMT inhibitors directly compete with cofactor occupying juxtaposed but distinct binding pockets Compounds must compete with high cellular levels of SAM.toIncross comparison, the substrate binding site, which relies on a high high cellular levels offor. Later studies showed some substrate-competing molecules, suchLater as clinical of some substrate-competing molecules, such asinteractions clinical inhibitors of PRMT5, were engaged in direct and PRMT5, were engaged in direct and critical with the bound cofactor to potently inhibit critical interactions with the bound cofactor to potently inhibit their target [16]. Structural chemistry chemistry of of methyltransferase methyltransferase inhibitors, cofactor-competing compounds and on cofactor-dependent substrate competitors.

Cofactor Competitors

Exploiting the Bound Cofactor

Type I PRMTs

Findings

Conclusions