- Synthesis and evaluation of bifunctional PTP4A3 phosphatase inhibitors activating the ER stress pathway
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We developed JMS-053, a potent inhibitor of the dual specificity phosphatase PTP4A3 that is potentially suitable for cancer therapy. Due to the emerging role of the unfolded protein response (UPR) in cancer pathology, we sought to identify derivatives that combine PTP4A3 inhibition with induction of endoplasmatic reticulum (ER) stress, with the goal to generate more potent anticancer agents. We have now generated bifunctional analogs that link the JMS-053 pharmacophore to an adamantyl moiety and act in concert with the phosphatase inhibitor to induce ER stress and cell death. The most potent compound in this series, 7a, demonstrated a ca. 5-fold increase in cytotoxicity in a breast cancer cell line and strong activation of UPR and ER stress response genes in spite of a ca. 13-fold decrease in PTP4A3 inhibition. These results demonstrate that the combination of phosphatase inhibition with UPR/ER-stress upregulation potentiates efficacy.
- Brodsky, Jeffrey L.,Hart, Duncan J.,Lazo, John S.,Rastelli, Ettore J.,Sannino, Sara,Sharlow, Elizabeth R.,Wipf, Peter
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supporting information
(2021/06/21)
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- IN-FLOW PHOTOOXYGENATION OF AMINOTHIENOPYRIDINONES GENERATES NOVEL PTP4A3 PHOSPHATASE INHIBITORS
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The disclosure provides compounds that inhibit protein tyrosine phosphatase, such as protein tyrosine phosphatase 4A3 (PTP4A3). The disclosure also provides pharmaceutical compositions, uses, and methods of using the compounds, such as in the treatment of cancers. (I), wherein X is O or NH.
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Paragraph 0084; 00100
(2020/06/05)
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- In-flow photooxygenation of aminothienopyridinones generates iminopyridinedione PTP4A3 phosphatase inhibitors
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A continuous flow photooxygenation of 7-aminothieno[3,2-c]pyridin-4(5H)-ones to produce 7-iminothieno[3,2-c]pyridine-4,6(5H,7H)-diones has been developed, utilizing ambient air as the sole reactant. N-H Imines are formed as the major products, and excellent functional group tolerance and conversion on gram-scale without the need for chromatographic purification allow for facile late-stage diversification of the aminothienopyridinone scaffold. Several analogs exhibit potent in vitro inhibition of the cancer-associated protein tyrosine phosphatase PTP4A3, and the SAR supports an exploratory docking model.
- Tasker, Nikhil R.,Rastelli, Ettore J.,Blanco, Isabella K.,Burnett, James C.,Sharlow, Elizabeth R.,Lazo, John S.,Wipf, Peter
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p. 2448 - 2466
(2019/03/06)
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- BENZAZEPINE DERIVATIVE, PREPARATION METHOD, PHARMACEUTICAL COMPOSITION AND USE THEREOF
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Disclosed are a benzazepine derivative, a preparation method, a pharmaceutical composition and the use thereof. A compound as shown in formula (I) of the present invention, and an isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof have the following structure. The benzazepine derivative of the present invention has a good regulation effect on the TLR family and the related signalling pathway, and in particular, has a good regulation effect on TLR8, can effectively treat, relieve and/or prevent various diseases mediated by TLR family and the TLR-related signalling pathway, and in particular, can effectively treat, relieve and/or prevent various diseases mediated by TLR8, such as cancers, autoimmune diseases, infections, inflammations, transplantation rejections, graft-versus-host diseases, etc.
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Paragraph 0153; 0164; 0165
(2019/03/29)
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- Identification of 2-(4-pyridyl)thienopyridinones as GSK-3β inhibitors
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The discovery of a novel series of 2-(4-pyridyl)thienopyridinone GSK-3β inhibitors is reported. X-ray crystallography reveals its binding mode and enables rationalization of the SAR. The initial optimization of the template for improved cellular activity and predicted CNS penetration is also presented.
- Gentile, Gabriella,Bernasconi, Giovanni,Pozzan, Alfonso,Merlo, Giancarlo,Marzorati, Paola,Bamborough, Paul,Bax, Benjamin,Bridges, Angela,Brough, Caroline,Carter, Paul,Cutler, Geoffrey,Neu, Margarete,Takada, Mia
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p. 4823 - 4827
(2011/09/21)
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- Antiinflammation agents
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Compounds, compositions and methods that are useful in the treatment of inflammatory, immunoregulatory, metabolic, infectious and cell proliferative diseases or conditions are provided herein. In particular, the invention provides compounds which modulate the expression and/or function of proteins involved in inflammation, metabolism, infection and cell proliferation. The subject compounds contain a fused heterobicyclic ring.
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Page/Page column 41
(2010/02/06)
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- NEW COMPOUNDS USEFUL FOR THE TREATMENT OF OBESITY, TYPE II DIABETES AND CNS DISORDERS
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The present invention relates to compounds of the general formula (I), wherein P is sulfone or sulfonamide; and A, B, W, X, Y and R3 are as defined in the description;to pharmaceutical compositions comprising these compounds, and to the use of the compounds for the prophylaxis and treatment of medical conditions relating to obesity, type II diabetes, and/or CNS disorders, to achieve reduction of body weight and of body weight gain.
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