Ro 90-7501 inhibits PP5 through a novel, TPR-dependent mechanism

Hong, Tae-Joon; Park, Kwanghyun; Choi, Eun-Wook; Hahn, Jinyong

doi:10.1016/j.bbrc.2016.11.043

Cited by 11 publications

(11 citation statements)

References 31 publications

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“…CGS 15943 is an adenosine nucleoside analog and adenosine receptor antagonist with pharmacological effects in mammals similar to caffeine (25,26). Ro 90-7501 has several previously identified mammalian cell activities: activating immune pattern recognition receptor signaling, inhibiting protein phosphatase 5, and interfering with amyloid β42 fibril assembly (27)(28)(29). CGS 15943 and Ro 90-7501 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Discovery of small-molecule inhibitors of multidrug-resistance plasmid maintenance using a high-throughput screening approach

Zulauf

2020

Proc. Natl. Acad. Sci. U.S.A.

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Carbapenem-resistant Enterobacteriaceae (CRE) are multidrug-resistant pathogens for which new treatments are desperately needed. Carbapenemases and other types of antibiotic resistance genes are carried almost exclusively on large, low-copy-number plasmids (pCRE). Accordingly, small molecules that efficiently evict pCRE plasmids should restore much-needed treatment options. We therefore designed a high-throughput screen to identify such compounds. A synthetic plasmid was constructed containing the plasmid replication machinery from a representativeEscherichia coliCRE isolate as well as a fluorescent reporter gene to easily monitor plasmid maintenance. The synthetic plasmid was then introduced into anE. coliK12tolChost. We used this screening strain to test a library of over 12,000 known bioactive agents for molecules that selectively reduce plasmid levels relative to effects on bacterial growth. From 366 screen hits we further validated the antiplasmid activity of kasugamycin, an aminoglycoside; CGS 15943, a nucleoside analog; and Ro 90-7501, a bibenzimidazole. All three compounds exhibited significant antiplasmid activity including up to complete suppression of plasmid replication and/or plasmid eviction in multiple orthogonal readouts and potentiated activity of the carbapenem, meropenem, against a strain carrying the large, pCRE plasmid from which we constructed the synthetic screening plasmid. Additionally, we found kasugamycin and CGS 15943 blocked plasmid replication, respectively, by inhibiting expression or function of the plasmid replication initiation protein, RepE. In summary, we validated our approach to identify compounds that alter plasmid maintenance, confer resensitization to antimicrobials, and have specific mechanisms of action.

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Section: Resultsmentioning

confidence: 99%

Discovery of small-molecule inhibitors of multidrug-resistance plasmid maintenance using a high-throughput screening approach

Zulauf

2020

Proc. Natl. Acad. Sci. U.S.A.

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“…ATM inhibitors may not increase the toxicity of irradiation to normal tissue. Herzog Recently, Ro 90-7501 has been reported to inhibit the action of protein phosphatase 5 (PP5), which is a serine/threonine phosphatase that belongs to the PPP family phosphatases (17). PP5 is known to play a role in ATM activation after irradiation (18).…”

Section: Discussionmentioning

confidence: 99%

Ro 90-7501 Is a Novel Radiosensitizer for Cervical Cancer Cells that Inhibits ATM Phosphorylation

Tamari

Sano

et al. 2019

Anticancer Res

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Background/Aim: Ro 90-7501 has been reported as an inhibitor of the amyloid β42 fibril assembly that is associated with Alzheimer's disease. The present study aimed to elucidate the radiosensitizing effects of Ro 90-7501 and focused on ATM signaling after irradiation. Materials and Methods: Clonogenic survival, apoptosis, and cell-cycle assays as well as western blotting were performed in HeLa cells treated with irradiation and Ro 90-7501. Tumor growth delay assay was also performed using BALB/c-nu mice. Results: The combination of irradiation with Ro 90-7501 showed significant radiosensitizing effects in clonogenic survival and tumor growth delay assays. Ro 90-7501 significantly increased apoptosis and impaired cell cycle after irradiation. Western blotting showed that Ro 90-7501 suppressed the phosphorylation of ATM and its downstream proteins, such as H2AX, Chk1, and Chk2, after irradiation. Conclusion: Ro 90-7501 inhibits DNA damage response by inhibiting ATM and has significant radiosensitizing effects on cervical cancer cells.Cervical cancer is one of the most common cancers among women worldwide, accounting for 569,847 new cases and 311,365 deaths annually (1). Radiotherapy has been commonly used in cervical cancer treatment for a long time, especially for locally advanced cancer. However, because treatment results are not satisfactory, development of radiosensitizers is one of the strategies to improve efficacy of radiotherapy. Although cisplatin is used as a radiosensitizer for locally advanced cervical cancer, patients often develop hematologic and gastrointestinal complications (2). Discovery for new radiosensitizers that are less toxic and more effective against cancer could improve treatment efficacy. In this study, we focused on the compound "Ro 90-7501", which is reported to be an inhibitor of amyloid β42 fibril assembly involved in Alzheimer's disease (3).Ataxia telangiectasia is caused by loss of ataxia telangiectasia mutated (ATM) function and is characterized by increased radiosensitivity (4). The ATM protein kinase is known as a tumor suppressor, which is frequently mutated in human cancers. ATM regulates cellular response to DNA double-strand breaks by phosphorylating various proteins such as Chk1, Chk2, and H2AX involved in DNA damage response and cell-cycle checkpoint activation after irradiation (5). Inhibition of DNA damage response can be effective in enhancing cytotoxicity after irradiation (6). In this context, the present study aimed to elucidate the effects of radiosensitization of Ro 90-7501 on DNA damage response through ATM signaling. Materials and MethodsCell culture. The human cervical cancer cell lines HeLa and ME-180 were purchased from American Type Culture Collection (VA, USA) and were cultured in Dulbecco's modified eagle's medium supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin, and 100 μg/ml streptomycin. Ro 90-7501 was purchased from Sigma (MO, USA) and dissolved in DMSO.Irradiation. Cells were irradiated under ambient conditions using a ceasium-137 ga...

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“…Highly selective PP5 inhibitors are desired so that this general toxicity can be avoided. It has been indicated that the similarity of phosphatase catalytic elements among PPP family phosphatases may contribute in part to the nonspecific inhibition . On the other hand, improving the potency of PP5 inhibitors also attracts extensive interest.…”

Section: Discussionmentioning

confidence: 99%

Serine/threonine protein phosphatase 5 is a potential therapeutic target in cholangiocarcinoma

Huang

Chao

et al. 2018

Liver International

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Ro 90-7501 inhibits PP5 through a novel, TPR-dependent mechanism

Cited by 11 publications

References 31 publications

Discovery of small-molecule inhibitors of multidrug-resistance plasmid maintenance using a high-throughput screening approach

Discovery of small-molecule inhibitors of multidrug-resistance plasmid maintenance using a high-throughput screening approach

Ro 90-7501 Is a Novel Radiosensitizer for Cervical Cancer Cells that Inhibits ATM Phosphorylation

Serine/threonine protein phosphatase 5 is a potential therapeutic target in cholangiocarcinoma

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