( R )-PFI-2 is a potent and selective inhibitor of SETD7 methyltransferase activity in cells

Abstract

Significance Protein methyltransferases constitute an emerging but undercharacterized class of therapeutic targets with diverse roles in normal human biology and disease. Small-molecule “chemical probes” can be powerful tools for the functional characterization of such enzymes, and here we report the discovery of ( R )-PFI-2—a first-in-class, potent, highly selective, and cell-active inhibitor of the methyltransferase activity of SETD7 [SET domain containing (lysine methyltransferase) 7]—and two related compounds for control and chemoproteomics studies. We used these compounds to characterize the role of SETD7 in signaling, in the Hippo pathway, that controls cell growth and organ size. Our work establishes a chemical biology tool kit for the study of the diverse roles of SETD7 in cells and further validates protein methyltransferases as a druggable target class.

S -adenosyl methionine is necessary for inhibition of the methyltransferase G9a by the lysine 9 to methionine mutation on histone H3

“…4 D-F). Previous studies identified small molecules that inhibited G9a and other SET domain methyltransferases in an uncompetitive manner with respect to SAM (19)(20)(21)(22). A detailed analysis of available crystallography data revealed that these uncompetitive compounds also selectively bound to SAM-occupied G9a like the peptides used in our study (Fig.…”

Metabolic Karma—The Atherogenic Legacy of Diabetes: The 2017 Edwin Bierman Award Lecture

“…These findings, confirmed in animal models exposed to transient hyperglycemia (54), provide the rationale to consider Set7 as an appropriate target for end-organ protective therapies in diabetes. Although specific Set7 inhibitors are currently unavailable for clinical development, the current interest in drugs that block various enzymes, such as Set7, that influence histone methylation in diseases, such as cancer (56), could lead to agents that warrant testing in diabetes. Studies addressing other sites of histone methylation as well as other epigenetic pathways including DNA methylation and acetylation have been reported or are currently in progress (55,57,58), particularly in the context of diabetes complications.…”

Methyltransferase inhibitors for modulation of the epigenome and beyond

“…Several groups identified a class of compounds sharing a pyridone pharmacophore as highly selective inhibitors of EZH2 [9,10,11,12,13,14]. Recently published chemical probes of other SET domain PKMTs include PFI-2, an inhibitor of SETD7 (one of the first characterized PMT) [15 ], the SMYD2 inhibitors LLY-507 and A-893 (an 82 Chemical Genetics and Epigenetics DNA incorporation followed by covalent target binding DNMT1 Azacitidine, decitabine [28] a Compounds of special and outstanding interest published in the past two years are respectively indicated with * and **. …”

“…The SETD7 selective inhibitor PFI-2 has contributed to better understanding of this enzyme in several pathways. PFI-2 altered Hippo pathway signaling at high cell density by rapidly increasing the nuclear localization of transcriptional coactivator YAP, and increased expression of YAP target genes [15 ]. PFI-2 was also used to demonstrate SETD7-mediated methylation of HIF1-a and consequent negative regulation of HIF-a transcriptional activity and HIF1-a-mediated glucose homeostasis [47].…”