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Identification of drug repurposing candidates for the treatment of polycystic kidney disease - RPTEC/TERT1 proteome

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease with limited treatment options. Drug repurposing offers a promising strategy to find effective treatments. We identified birinapant, bardoxolone methyl and salicylic acid as repurposing candidates for ADPKD and applied thermal proteome profiling to identify disease-relevant targets. Our results uncovered shared effects between the three drugs, including a thermal shift in ADP/ATP translocases (SLC25A4/5/6) caused by reduced ATP production. As expected, salicylic acid displayed a polypharmacological profile but also engaged enzymes along the N-linked glycosylation pathway and inhibited PTK2, an activator of the proliferative PI3K/Akt/mTOR pathway. Orthogonal assays and computational modelling confirmed these findings and located the binding site (499-504) of salicylic acid within PTK2’s ATP-binding pocket. Engagement of several targets was achieved at clinically relevant concentrations.We have identified novel targets of three repurposing candidates that contribute to the cyst growth reducing effects in preclinical ADPKD models and identify salicylic acid, the metabolite of aspirin, as the repurposing candidate with the most promising mechanisms of action.This dataset contains files from the global protein analysis of RPTEC/TERT1 cells cultured on TC-inserts under physiological (10%; PO) and atmospheric (21%; AO) oxygen tension.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Kidney

SUBMITTER: Alina Meyer

LAB HEAD: Per Artursson

PROVIDER: PXD063670 | Pride | 2026-05-18

REPOSITORIES: Pride

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			Action	DRS
	87_NCLAOTr1_1.raw	Raw
	87_NCLAOTr1_2.raw	Raw
	87_NCLAOTr1_3.raw	Raw
	88_NCLAOTr2_1.raw	Raw
	88_NCLAOTr2_2.raw	Raw

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Similar Datasets

Identification of drug repurposing candidates for the treatment of polycystic kidney disease - Salicylic acid

Project description:Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease with limited treatment options. Drug repurposing offers a promising strategy to find effective treatments. We identified birinapant, bardoxolone methyl and salicylic acid as repurposing candidates for ADPKD and applied thermal proteome profiling to identify disease-relevant targets. Our results uncovered shared effects between the three drugs, including a thermal shift in ADP/ATP translocases (SLC25A4/5/6) caused by reduced ATP production. As expected, salicylic acid displayed a polypharmacological profile but also engaged enzymes along the N-linked glycosylation pathway and inhibited PTK2, an activator of the proliferative PI3K/Akt/mTOR pathway. Orthogonal assays and computational modelling confirmed these findings and located the binding site (499-504) of salicylic acid within PTK2’s ATP-binding pocket. Engagement of several targets was achieved at clinically relevant concentrations. We have identified novel targets of three repurposing candidates that contribute to the cyst growth reducing effects in preclinical ADPKD models and identify salicylic acid, the metabolite of aspirin, as the repurposing candidate with the most promising mechanisms of action.This dataset contains files from thermal proteome profiling after salicylic acid exposure.

2026-05-18 | PXD063666 | Pride

Identification of drug repurposing candidates for the treatment of polycystic kidney disease - Birinapant

Project description:Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease with limited treatment options. Drug repurposing offers a promising strategy to find effective treatments. We identified birinapant, bardoxolone methyl and salicylic acid as repurposing candidates for ADPKD and applied thermal proteome profiling to identify disease-relevant targets. Our results uncovered shared effects between the three drugs, including a thermal shift in ADP/ATP translocases (SLC25A4/5/6) caused by reduced ATP production. As expected, salicylic acid displayed a polypharmacological profile but also engaged enzymes along the N-linked glycosylation pathway and inhibited PTK2, an activator of the proliferative PI3K/Akt/mTOR pathway. Orthogonal assays and computational modelling confirmed these findings and located the binding site (499-504) of salicylic acid within PTK2’s ATP-binding pocket. Engagement of several targets was achieved at clinically relevant concentrations. We have identified novel targets of three repurposing candidates that contribute to the cyst growth reducing effects in preclinical ADPKD models and identify salicylic acid, the metabolite of aspirin, as the repurposing candidate with the most promising mechanisms of action. This dataset contains files from thermal proteome profiling after birinapant exposure.

2026-05-18 | PXD063662 | Pride

Identification of drug repurposing candidates for the treatment of polycystic kidney disease - Bardoxolone methyl

Project description:Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease with limited treatment options. Drug repurposing offers a promising strategy to find effective treatments. We identified birinapant, bardoxolone methyl and salicylic acid as repurposing candidates for ADPKD and applied thermal proteome profiling to identify disease-relevant targets. Our results uncovered shared effects between the three drugs, including a thermal shift in ADP/ATP translocases (SLC25A4/5/6) caused by reduced ATP production. As expected, salicylic acid displayed a polypharmacological profile but also engaged enzymes along the N-linked glycosylation pathway and inhibited PTK2, an activator of the proliferative PI3K/Akt/mTOR pathway. Orthogonal assays and computational modelling confirmed these findings and located the binding site (499-504) of salicylic acid within PTK2’s ATP-binding pocket. Engagement of several targets was achieved at clinically relevant concentrations. We have identified novel targets of three repurposing candidates that contribute to the cyst growth reducing effects in preclinical ADPKD models and identify salicylic acid, the metabolite of aspirin, as the repurposing candidate with the most promising mechanisms of action. This dataset contains files from thermal proteome profiling after bardoxolone methyl exposure.

2026-05-18 | PXD063660 | Pride

A patient-derived 3D cyst model of polycystic kidney disease that mimics disease development, expresses relevant drug targets and responds to repurposing candidates

Project description:Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Its progressively expanding, fluid-filled renal cysts eventually lead to end-stage renal disease. Despite the relatively high prevalence, treatment options are currently limited to a single drug approved by the FDA and EMA. Here, we investigated human ADPKD patient-derived three-dimensional cyst cultures (3DCC) as an in vitro model for ADPKD and drug repurposing research. First, we analyzed the proteomes of 3DCC derived from healthy and diseased tissues. We then compared the protein expression profiles with those of reference tissues, mainly from the same patients. We quantified 290 proteins affecting drug disposition and proposed target proteins for drug treatment. Lastly, we investigated the functional response of the quantified target proteins after exposure to repurposing candidates in the 3DCC. Proteomic profiling of human 3DCC reflected previously reported pathophysiological alterations, including aberrant protein expression in inflammation and metabolic reprogramming. While the 3DCCs largely recapitulated the disease phenotype in vitro, drug transporter expression was reduced compared to in vivo conditions. Target proteins for proposed repurposing candidates showed similar expression in vitro and in tissues. Exposure to these repurposing candidates inhibited cyst swelling in vitro, supporting the suitability of the 3DCC for ADPKD drug screening. In summary, our results provide new insights into the ADPKD proteome and offer a starting point for further research to improve treatment options for affected individuals.

2025-05-06 | PXD056281 | Pride

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Project description:In this study we aimed to identify off-targets of polo-like kinase 1 (Plk1) small molecule inhibitor volasertib. Plk1 is an important cell cycle kinase and an attractive target for anticancer treatment. Volasertib is ATP-competitive small molecules that may also block the ATP-pocket of other proteins. Despite the fatal infections and negative survival in a phase III trial on volasertib in acute myeloid leukemia volasertib has been a promising treatment option in children with rhabdomyosarcoma. Therefore, there is a need to understand the nature of adverse effects that possibly originate from the off-target proteins. We used thermal proteome profiling (TPP) to identify proteins that have a change in the thermal stability after treatment with volasertib. The temperature of aggregation of several proteins involved in prostaglandin and phosphatidyl-inositol phosphate metabolism increased after treatment with volasertib. PIP4K2A and ZADH2 were stabilized both by treatment in living cells and cell lysate. Functional disruption of these proteins affects the immune response and fatty acid metabolism. In addition, volasertib was found to affect transcriptional coactivators, normal and alternative RNA splicing regulators and proteins involved in the intracellular transport regulation. Our data suggests that the identified proteins may contribute more to the understanding of anti-tumor effect of volasertib.

2021-08-23 | PXD023757 | Pride

Gene expression in early phases of Autosomal Dominant Polycystic Kidney Disease

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