SGC707

SGC707 is a selective, potent, low molecular weight (MW = 298) and cell-active allosteric inhibitor of protein arginine N-methyltransferase 3 (PRMT3). PRMT3, one of the four type I protein arginine N-methyltransferases, has been implicated in ribosomal biosynthesis via catalyzing the formation of asymmetric (type I) mono- and dimethylarginine. PRMT3 has also been involved in cancer via interaction with the DAL-1 tumor suppressor protein [1]. SGC707 inhibits the activity of PRMT3 by targeting the dimerization interface of PRMT3[2].

In vitro: The IC50 and KD value of SGC707 against PRMT3was 31 ± 2 nM and 53 ± 2 nM respectively. SGC707 showed an outstanding selectivity for PRMT3 against 31 other methyltransferases and a broad range of 250 non-epigenetic targets, G protein-coupled receptors (GPCRs), ion channels, and transporters. The residence time of SGC707 was 9.7 min. In both HEK293 and A549 cells, SGC707 stabilized PRMT3 with EC50 values of 1.3 μM and 1.6 μM, respectively. SGC707 treatment at high concentrations 50 and 100 mM for 72 h lead to some toxicity [1].

In vivo: In CD-1 male mice, intraperitoneal injection of SGC707 at 30 mg/kg for over 6 h showed good plasma exposure with the peak plasma level of 38 ?M. After injection 6 h, the plasma level of SGC707 decreased to 208 nM. The half-life of SGC707 was about 1 h. The 30 mg/kg dose was well tolerated in the tested mouse model [1].

References:
Kaniskan H ?, Szewczyk M M, Yu Z, et al.  A Potent, Selective and Cell‐Active Allosteric Inhibitor of Protein Arginine Methyltransferase 3 (PRMT3)[J]. Angewandte Chemie International Edition, 2015, 54(17): 5166-5170.
Luo M.  Inhibitors of protein methyltransferases as chemical tools[J]. Epigenomics, 2015, 7(8): 1327-1338.

Inhibition of PRMT3 activity reduces hepatic steatosis without altering atherosclerosis susceptibility in apoE knockout mice.[Pubmed:30776415]

Biochim Biophys Acta Mol Basis Dis. 2019 Feb 15. pii: S0925-4439(19)30064-X.

The nuclear receptor liver X receptor (LXR) impacts on cholesterol metabolism as well as hepatic lipogenesis via transcriptional regulation. It is proposed that inhibition of the protein arginine methyltransferase 3 (PRMT3) uncouples these two transcriptional pathways in vivo by acting as a specific lipogenic coactivator of LXR. Here we validated the hypothesis that treatment with the allosteric PRMT3 inhibitor SGC707 will diminish the hepatic steatosis extent, while leaving global cholesterol metabolism, important in cholesterol-driven pathologies like atherosclerosis, untouched. For this purpose, 12-week old hyperlipidemic apolipoprotein E knockout mice were fed a Western-type diet for six weeks to induce both hepatic steatosis and atherosclerosis. The mice received 3 intraperitoneal injections with SGC707 or solvent control per week. Mice chronically treated with SGC707 developed less severe hepatic steatosis as exemplified by the 51% reduced (P<0.05) liver triglyceride levels. In contrast, the extent of in vivo macrophage foam cell formation and aortic root atherosclerosis was not affected by SGC707 treatment. Interestingly, SGC707-treated mice gained 94% less body weight (P<0.05), which was paralleled by changes in white adipose tissue morphology, i.e. reduction in adipocyte size and browning. In conclusion, we have shown that through PRMT3 inhibitor treatment specific functions of LXR involved in respectively the development of fatty liver disease and atherosclerosis can be uncoupled, resulting in an overall diminished hepatic steatosis extent without a negative impact on atherosclerosis susceptibility. As such, our studies highlight that PRMT3 inhibition may constitute a novel therapeutic approach to limit the development of fatty liver disease in humans.

Inhibition of protein arginine methyltransferase 3 activity selectively impairs liver X receptor-driven transcription of hepatic lipogenic genes in vivo.[Pubmed:29774529]

Br J Pharmacol. 2018 Aug;175(15):3175-3183.

BACKGROUND AND PURPOSE: Agonists for the liver X receptor (LXR) are considered promising therapeutic moieties in cholesterol-driven diseases by promoting cellular cholesterol efflux pathways. However, current clinical application of these agents is hampered by concomitant LXR-induced activation of a lipogenic transcriptional network, leading to hepatic steatosis. Recent studies have suggested that protein arginine methyltransferase 3 (PRMT3) may act as a selective co-activator of LXR activity. Here, we verified the hypothesis that PRMT3 inhibition selectively disrupts the ability of LXR to stimulate lipogenesis while maintaining its capacity to modulate macrophage cholesterol homeostasis. EXPERIMENTAL APPROACH: A combination of the LXR agonist T0901317 and palm oil was administered to C57BL/6 mice to maximally stimulate LXR and PRMT3 activity. PRMT3 activity was inhibited using the allosteric inhibitor SGC707. KEY RESULTS: Treatment with SGC707 did not negatively influence the T0901317/palm oil-induced up-regulation of the cholesterol efflux ATP-binding cassette transporter genes, ABCA1 and ABCG1, in peritoneal cells. In contrast, SGC707 treatment was associated with a significant decrease in the hepatic expression of the lipogenic gene fatty acid synthase (-64%). A similar trend was observed for stearoyl-coenzyme A desaturase and acetyl CoA carboxylase expression (-43%; -56%). This obstruction of lipogenic gene transcription coincided with a significant 2.3-fold decrease in liver triglyceride content as compared with the T0901317 and palm oil-treated control group. CONCLUSION AND IMPLICATIONS: We showed that inhibition of PRMT3 activity by SGC707 treatment selectively impairs LXR-driven transcription of hepatic lipogenic genes, while the positive effect of LXR stimulation on macrophage cholesterol efflux pathways is maintained.

A potent, selective and cell-active allosteric inhibitor of protein arginine methyltransferase 3 (PRMT3).[Pubmed:25728001]

Angew Chem Int Ed Engl. 2015 Apr 20;54(17):5166-70.

PRMT3 catalyzes the asymmetric dimethylation of arginine residues of various proteins. It is essential for maturation of ribosomes, may have a role in lipogenesis, and is implicated in several diseases. A potent, selective, and cell-active PRMT3 inhibitor would be a valuable tool for further investigating PRMT3 biology. Here we report the discovery of the first PRMT3 chemical probe, SGC707, by structure-based optimization of the allosteric PRMT3 inhibitors we reported previously, and thorough characterization of this probe in biochemical, biophysical, and cellular assays. SGC707 is a potent PRMT3 inhibitor (IC50 =31+/-2 nM, KD =53+/-2 nM) with outstanding selectivity (selective against 31 other methyltransferases and more than 250 non-epigenetic targets). The mechanism of action studies and crystal structure of the PRMT3-SGC707 complex confirm the allosteric inhibition mode. Importantly, SGC707 engages PRMT3 and potently inhibits its methyltransferase activity in cells. It is also bioavailable and suitable for animal studies. This well-characterized chemical probe is an excellent tool to further study the role of PRMT3 in health and disease.

SGC707 is a first-in-class PRMT3 chemical probe which is a potent, selective, and cell-active allosteric inhibitor of PRMT3 with IC50 of 31 nM.

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