Discovery and characterization of halogenated xanthene inhibitors of DUSP5 as potential photodynamic therapeutics

Bongard, Robert D.; Lepley, Michael; Gastonguay, Adam; Syrlybaeva, Raulia; Talipov, Marat R.; Lipinski, Rachel A. Jones; Leigh, Noah R.; Brahmbhatt, Jaladhi; Kutty, Raman G.; Rathore, Rajendra; Ramchandran, Ramani; Sem, Daniel S.

doi:10.1016/j.jphotochem.2019.01.005

Cited by 12 publications

(4 citation statements)

References 30 publications

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“…Two classes of DUSP5 inhibitors have been described: compounds contain or are similar to naphthalene trisulfonate core, such as suramin, a Food and Drug Administration-approved drug for the treatment of African sleeping sickness, and a small molecule, CSD 3 -2320, that binds to the C-terminal phosphatase domain of DUSP5 to block its phosphatase effect (Neumann et al, 2015). More recently, halogenated xanthene inhibitors of DUSP5 were discovered (Bongard et al, 2019). These xanthene-ring analogs inhibit DUSP5 phosphatase domain activity in vitro with IC 50 values in the micromolar range and relative potency of rose bengal .…”

Section: Discussionmentioning

confidence: 99%

Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension-Induced Renal Injury

Zhang

Murphy

et al. 2019

J Pharmacol Exp Ther

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Dual-specificity protein phosphatase 5 (DUSP5) is a member of the tyrosine-threonine phosphatase family with the ability to dephosphorylate and inactivate extracellular signal-related kinase (ERK). The present study investigates whether knockout (KO) of Dusp5 improves renal hemodynamics and protects against hypertension-induced renal injury. The renal expression of DUSP5 was reduced, and the levels of phosphorylated (p) ERK1/2 and p-protein kinase C (PKC) a were elevated in the KO rats. KO of Dusp5 enhanced the myogenic tone of the renal afferent arteriole and interlobular artery in vitro with or without induction of deoxycorticosterone acetate-salt hypertension. Inhibition of ERK1/2 and PKC diminished the myogenic response to a greater extent in Dusp5 KO rats. Autoregulation of renal blood flow was significantly impaired in hypertensive wild-type (WT) rats but remained intact in Dusp5 KO animals. Proteinuria was markedly decreased in hypertensive KO versus WT rats. The degree of glomerular injury was reduced, and the expression of nephrin in the glomerulus was higher in hypertensive Dusp5 KO rats. Renal fibrosis and medullary protein cast formation were attenuated in hypertensive Dusp5 KO rats in association with decreased expression of monocyte chemoattractant protein 1, transforming growth factor-b1, matrix metalloproteinase (MMP) 2, and MMP9. These results indicate that KO of Dusp5 protects against hypertension-induced renal injury, at least in part, by maintaining the myogenic tone of the renal vasculature and extending the range of renal blood flow autoregulation to higher pressures, which diminish glomerular injury, protein cast formation, macrophage infiltration, and epithelial-mesenchymal transformation in the kidney. SIGNIFICANCE STATEMENT Dual-specificity protein phosphatase 5 (DUSP5) is a tyrosinethreonine phosphatase that inactivates extracellular signalrelated kinase (ERK). We previously reported that knockout (KO) of Dusp5 enhanced the myogenic response and autoregulation in the cerebral circulation. The present study investigates whether KO of DUSP5 improves renal hemodynamics and protects against hypertension-induced renal injury. Downregulation of DUSP5 enhanced the myogenic tone of renal arteriole and artery and autoregulation of renal blood flow in association with reduced proteinuria, glomerular injury, and interstitial fibrosis after the induction of hypertension. Inhibition of ERK1/2 and protein kinase C diminished the myogenic response to a greater extent in Dusp5 KO rats. These results suggest that DUSP5 might be a viable drug target for the treatment of hypertension nephropathy.

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Section: Discussionmentioning

confidence: 99%

Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension-Induced Renal Injury

Zhang

Murphy

et al. 2019

J Pharmacol Exp Ther

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“…Given the role of DUSPs in regulation of MAPK signaling and consequently autophagy activity, we investigated whether HPV16 E7-mediated DUSP5 deficiency activates autophagy. We incubated NHEKs with increasing concentrations of rose bengal, which is an FDA-approved compound with strong potency against DUSP5 [ 34 ], and showed by Western analysis that DUSP5 protein levels were indeed decreased in a rose bengal concentration-dependent manner (Figures 2(a) and 2(b) ). We furthermore investigated its impact on the autophagy activity marker proteins LC3 and p62.…”

Section: Resultsmentioning

confidence: 99%

Human Papillomavirus Type 16 Early Protein E7 Activates Autophagy through Inhibition of Dual-Specificity Phosphatase 5

Hua

Zheng

Zhu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Consistent high-risk human papillomavirus (HPV) infection leads to various malignant cancers. Autophagy can promote cancer progression by helping cancer cells survive under stress or induce oncogenic effects when mutations or abnormalities occur. Mitogen activated protein kinases (MAPKs) can transduce various external or intrinsic stimuli into cellular responses, including autophagy, and dual-specificity phosphates (DUSPs) contribute to the direct regulation of MAPK activities. Previously, we showed that expression of DUSP5 was repressed in HPV16 E7-expressing normal human epidermal keratinocytes (NHEKs). Here we show that clinical HPV16 E7-positive precancerous and cancerous tissues also demonstrate low DUSP5 levels compared with control tissues, indicating that the inverse correlation between HPV16 E7 and DUSP5 is clinically relevant. We furthermore investigated the autophagy response in both DUSP5-deficient and HPV16 E7-expressing NHEKs. Confocal microscopy and Western analysis showed induction of LC3-II levels, autophagosome formation and autophagy fluxes in DUSP5-deficient NHEKs. Furthermore, Western analysis demonstrated specific induction of phosphorylated ERK in DUSP5-deficient and HPV16 E7-expressing NHEKs, indicating that HPV16 E7-mediated repression of DUSP5 results in induced MAPK/ERK signaling. Finally, phosphorylated mTOR and ULK (S757) were reduced in DUSP5-deficient NHEKs, while phosphorylated ULK (S555) and AMPK were increased, thereby inducing canonical autophagy through the mTOR and AMPK pathways. In conclusion, our results demonstrate that HPV16 E7 expression reduces DUSP5 levels, which in turn results in active MAPK/ERK signaling and induction of canonical autophagy through mTOR and MAPK regulation. Given its demonstrated inverse correlation with clinical cancerous tissues, DUSP5 may serve as a potential therapeutic target for cervical cancer.

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“…The FHH.1 BN congenic rat was created by transferring a small segment of chromosome 1 from the Brown Norway rat into the Fawn Hooded hypertensive (FHH) genetic background, which contained 15 genes including Dusp5 , [ 26 , 37 ] although we have reported that the FHH rat is a potential ADRD model [ 59 – 62 ]. Future study is necessary to confirm whether DUSP5 expression is elevated in models of AD/ADRD, and whether the downregulation of DUSP5 expression or the use of DUSP5 inhibitors, such as compounds containing a naphthalene trisulfonate core, [ 63 ] or halogenated xanthene inhibitors of DUSP5, can enhance CBF and cognitive function in individuals with AD/ADRD [ 64 ]. Capillary stalling is another vascular mechanism that contributes to cerebral hypoperfusion in AD by causing neutrophil arrest and increasing the expression of inflammatory adhesion molecules in capillaries [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Enhanced Cerebral Hemodynamics and Cognitive Function Via Knockout of Dual-Specificity Protein Phosphatase 5

Zhang¹,

Border²,

Fang³

et al. 2023

J Pharm Pharmacol Res

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Alzheimer’s Disease (AD) and Alzheimer’s Disease-Related Dementias (ADRD) are neurodegenerative disorders. Recent studies suggest that cerebral hypoperfusion is an early symptom of AD/ADRD. Dual-specificity protein phosphatase 5 (DUSP5) has been implicated in several pathological conditions, including pulmonary hypertension and cancer, but its role in AD/ADRD remains unclear. The present study builds on our previous findings, demonstrating that inhibition of ERK and PKC leads to a dose-dependent dilation of the middle cerebral artery and penetrating arteriole, with a more pronounced effect in Dusp5 KO rats. Both ERK and PKC inhibitors resulted in a significant reduction of myogenic tone in vessels from Dusp5 KO rats. Dusp5 KO rats exhibited stronger autoregulation of the surface but not deep cortical cerebral blood flow. Inhibition of ERK and PKC significantly enhanced the contractile capacity of vascular smooth muscle cells from both strains. Finally, a significant improvement in learning and memory was observed in Dusp5 KO rats 24 hours after initial training. Our results suggest that altered vascular reactivity in Dusp5 KO rats may involve distinct mechanisms for different vascular beds, and DUSP5 deletion could be a potential therapeutic target for AD/ADRD. Further investigations are necessary to determine the effects of DUSP5 inhibition on capillary stalling, blood-brain barrier permeability, and neurodegeneration in aging and disease models.

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Discovery and characterization of halogenated xanthene inhibitors of DUSP5 as potential photodynamic therapeutics

Cited by 12 publications

References 30 publications

Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension-Induced Renal Injury

Knockout of Dual-Specificity Protein Phosphatase 5 Protects Against Hypertension-Induced Renal Injury

Human Papillomavirus Type 16 Early Protein E7 Activates Autophagy through Inhibition of Dual-Specificity Phosphatase 5

Enhanced Cerebral Hemodynamics and Cognitive Function Via Knockout of Dual-Specificity Protein Phosphatase 5

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