Development of Potent Type I Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation

Wang, Chen; Jiang, Hao; Jin, Junhong; Xie, Yiqian; Chen, Zhifeng; Zhang, Hao; Lian, Fulin; Liu, Yu-Chih; Zhang, Chenhua; Ding, Hong; Chen, Shijie; Zhang, Naixia; Zhang, Yuanyuan; Jiang, Hualiang; Chen, Kaixian; Ye, Fei; Yao, Zhiyi; Luo, Cheng

doi:10.1021/acs.jmedchem.7b01134

Cited by 44 publications

(47 citation statements)

References 65 publications

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“…The same operation was performed in sham mice except for the ligation of ureter. A total of 29 mice were randomly divided into 4 groups: 1) sham + vehicle (saline) group (n = 7), 2) UUO + vehicle group (n = 7), 3) sham + PT1001B [30 mg/kg, synthesized by Wang et al (5)] group (n = 7), and 4) UUO + PT1001B (30 mg/kg) group (n = 8). One day after the surgery, mice were treated with saline or 30 mg/kg PT1001B daily by intraperitoneal injection for 13 d. Kidney tissues were collected after euthanization at 14 d after the operation.…”

Section: Animal Studiesmentioning

confidence: 99%

“…Asymmetric dimethylarginine (ADMA) is a potent endogenous inhibitor of NOS, which can be produced by type I protein arginine methyltransferases (PRMTs) or inactivated by dimethylarginine dimethylaminohydrolase (DDAH) (5,6). Circulating ADMA is a strong predictor for the progression of CKD (7,8).…”

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confidence: 99%

“…Type I PRMTs consist of 4 enzymes, among which PRMT1 is the predominant type I methyltransferase accounting for ;90% of all cellular arginine methylation events (5). PT1001B (formerly named Compound 28d, DCPR049_12) is a novel selective inhibitor of type I PRMTs, and it effectively displayed inhibition on proliferation of cancer cells, which was correlated with reduced cellular asymmetric arginine dimethylation levels, including histone H4 arginine 3 asymmetric dimethylation (H4R3me2a) (5).…”

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confidence: 99%

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Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys

Peng

Lin

et al. 2019

FASEB j.

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The role of asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD) is unclear. Through inhibition of type I protein arginine methyltransferases (PRMTs), a novel strategy, we aimed to determine the effect of ADMA on renal fibrosis and explore its underlying working mechanisms. After sham or unilateral ureter ligation (UUO) operation, 20–25 g male c57 mice were treated with vehicle or PT1001B, an inhibitor of type I PRMTs, for 13 d. Moreover, human kidney 2 (HK2) and normal rat kidney 49F (NRK‐49F) cells were treated with various concentrations of PT1001B or ADMA in the presence of 2.5 ng/ml TGF‐β. We found that treatment with PT1001B increased the deposition of extracellular matrix proteins, the expression of αsmooth muscle actin, and connective tissue growth factor in UUO‐induced fibrotic kidneys, which is correlated with reduced expression of PRMT1, reduced the production of ADMA, and increased expression of uromodulin. In TGF‐β‐stimulated HK2 and NRK‐49F cells, PT1001B dose‐dependently inhibited ADMA production, increased NO concentrations, and enhanced the expression of profibrotic proteins. Exogenous addition of ADMA inhibited the expression of profibrotic proteins dose‐dependently and attenuated the profibrotic effect of PT1001B. Moreover, ADMA reduced the NO concentration in PT1001B‐treated HK2 cells. Finally, we conclude that ADMA has an antifibrotic effect in obstructed kidneys, and future application of type I PRMT inhibitor should be done cautiously for patients with CKD.—Wu, M., Lin, P., Li, L., Chen, D., Yang, X., Xu, L., Zhou, B., Wang, C., Zhang, Y., Luo, C., Ye, C. Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys. FASEB J. 33, 6948–6956 (2019). http://www.fasebj.org

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Section: Animal Studiesmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys

Peng

Lin

et al. 2019

FASEB j.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Avasarala

Khan

et al. 2020

Molecular Cancer Research

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Increased expression of protein arginine methyl transferase 6 (PRMT6) correlates with worse prognosis in lung cancer cases. To interrogate the in vivo functions of PRMT6 in lung cancer, we developed a tamoxifen-inducible lung-targeted PRMT6 gain-offunction mouse model, which mimics PRMT6 amplification events in human lung tumors. Lung-targeted overexpression of PRMT6 accelerated cell proliferation de novo and potentiated chemical carcinogen (urethane)-induced lung tumor growth. To explore the molecular mechanism/s by which PRMT6 promotes lung tumor growth, we used proteomics-based approaches and identified interleukin-enhancer binding protein 2 (ILF2) as a novel PRMT6-associated protein. Furthermore, by using a series of in vitro gain-of-function and loss-of-function experiments, we defined a new role for the PRMT6-ILF2 signaling axis in alternate activation of tumor-associated macrophages (TAM). Interestingly, we have also identified macrophage migration inhibitory factor, which has recently been shown to regulate alternate activation of TAMs, as an important downstream target of PRMT6-ILF2 signaling. Collectively, our findings reveal a previously unidentified noncatalytic role for PRMT6 in potentiating lung tumor progression via the alternate activation of TAMs. Implications: This is the first study to demonstrate an in vivo role for PRMT6 in lung tumor progression via the alternate activation of TAMs.

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“…Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor that is produced by type I protein arginine methyltransferases (PRMTs) and metabolized by dimethylarginine dimethylaminohydroxylase (DDAH), which consists of two isoforms, DDAH1 and DDAH2 [7][8][9]. Several in vivo and clinical studies have indicated that circulating ADMA is a risk factor and profibrotic in CKDs [10,11].…”

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confidence: 99%

Renal asymmetric dimethylarginine inhibits fibrosis

Yuan

Yanzhe

et al. 2020

FEBS Open Bio

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Chronic kidney disease (CKD) is a worldwide public health problem that is caused by repeated injuries to the glomerulus or renal tubules. Renal fibrosis commonly accompanies CKD, and it is histologically characterized by excessive deposition of extracellular matrix proteins, such as fibronectin and collagen I, in interstitial areas. Indirect in vivo experimental data suggest that renal asymmetric dimethylarginine (ADMA) exerts antifibrotic activity in CKD. In this study, we aimed to demonstrate that renal ADMA has a direct effect on fibrosis in vivo . Normal saline, ADMA, nonsense control siRNA, Ddah1 siRNA or Ddah2 siRNA was administered into the kidney through the left ureter in a mouse model of unilateral ureteral obstruction (UUO). UUO kidneys were harvested at day 1 or 7. Western blotting was performed to assess the expression of ADMA, DDAH1 and DDAH2 and the expression of fibrotic markers, such as fibronectin, collagen I, α‐smooth muscle actin, phosphorylation of Smad3 and connective tissue growth factor. Masson’s trichrome staining was used to further evaluate renal fibrosis. We observed that intrarenal administration of ADMA increased the renal accumulation of ADMA and attenuated renal fibrosis at days 1 and 7. Knockdown of Ddah1 or Ddah2 increased the amount of ADMA in UUO kidneys and inhibited the expression of fibrotic proteins at days 1 and 7, which was further confirmed by Masson’s staining. Thus, our in vivo data suggest that renal ADMA exerts direct antifibrotic effects in a mouse model of UUO.

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Development of Potent Type I Protein Arginine Methyltransferase (PRMT) Inhibitors of Leukemia Cell Proliferation

Cited by 44 publications

References 65 publications

Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys

Reduced asymmetric dimethylarginine accumulation through inhibition of the type I protein arginine methyltransferases promotes renal fibrosis in obstructed kidneys

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

Renal asymmetric dimethylarginine inhibits fibrosis

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