- 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.
- Rastelli, Ettore J.,Sannino, Sara,Hart, Duncan J.,Sharlow, Elizabeth R.,Lazo, John S.,Brodsky, Jeffrey L.,Wipf, Peter
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supporting information
(2021/06/21)
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- POLYCYCLIC COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES
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The present disclosure relates to bifunctional compounds, ULM— L—PTM, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A- RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 0653; 0654
(2020/03/29)
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- COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF RAPIDLY ACCELERATED FIBROSARCOMA POLYPEPTIDES
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The present disclosure relates to bifunctional compounds, which find utility as modulators of Rapidly Accelerated Fibrosarcoma (RAF, such as c-RAF, A-RAF and/or B-RAF; the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein RAF, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein, or the constitutive activation of the target protein, are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 1380
(2018/07/15)
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- Identification of the First PPARα/γ Dual Agonist Able to Bind to Canonical and Alternative Sites of PPARγ and to Inhibit Its Cdk5-Mediated Phosphorylation
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A new series of derivatives of the PPARα/γ dual agonist 1 allowed us to identify the ligand (S)-6 as a potent partial agonist of both PPARα and γ subtypes. X-ray studies in PPARγ revealed two different binding modes of (S)-6 to the canonical site. However
- Laghezza, Antonio,Piemontese, Luca,Cerchia, Carmen,Montanari, Roberta,Capelli, Davide,Giudici, Marco,Crestani, Maurizio,Tortorella, Paolo,Peiretti, Franck,Pochetti, Giorgio,Lavecchia, Antonio,Loiodice, Fulvio
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p. 8282 - 8298
(2018/09/27)
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- HETEROCYCLIC COMPOUND
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The present invention provides a compound having a superior JAK inhibitory action, which is useful as an agent for the prophylaxis or treatment of autoimmune diseases (rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, etc.), cancer (leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis, etc.) and the like, or a salt thereof. The present invention relates to a compound represented by the formula wherein each symbol is as defined in the specification, or a salt thereof.
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Paragraph 0885
(2015/04/15)
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- AMINO ALCOHOL DERIVATIVE, MEDICINAL COMPOSITION CONTAINING THE SAME, AND USE OF THESE
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The present invention provides compounds represented by general formula (I): a prodrug thereof, or pharmaceutical acceptable salts thereof, wherein R1 is hydrogen or lower alkyl; each of R2 and R3 is independently hydrogen or lower alkyl; each of R4, R5 and R6 is independently hydrogen, halogen, lower alkyl or lower alkoxy; R7 is hydrogen or lower alkyl; R8 is hydrogen, halogen, lower alkyl, lower alkoxy, etc; R9 is -COR10, -A1-COR10, -O-A2-COR10, etc; Ar is optionally substituted phenyl or heteroaryl; and A is a bond, -OCH2-, etc, which exhibit potent and selective β3-adrenoceptor stimulating activities. The present invention also provides pharmaceutical compositions containing said compound, and uses thereof.
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Page/Page column 38-39
(2008/06/13)
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- AMINO ALCOHOL DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME, AND USE THEREOF
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The present invention provides compounds represented by general formula (I): or pharmaceutical acceptable salts thereof, wherein R1 and R2 are each hydrogen or lower alkyl; R3 R4, R5 and R6 are each hydrogen, halogen, lower alkyl or lower alkoxy; R7 and R8 are each hydrogen, halogen, lower alkyl, halo-lower alkyl, lower alkoxy, cycloalkyl, aryl, heteroaryl, cyano, a hydroxyl group, lower acyl, carboxy or the like; R9 is -C(O)-R10, -A1-C(O)-R10, -O-A2-C(O)-R10 or a tetrazol-5-yl group, which exhibit potent and selective β3-adrenoceptor stimulating activities. The present invention also provides pharmaceutical compositions containing said compound, and uses thereof.
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Page/Page column 35
(2008/06/13)
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- AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
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Aminopyridine and aminopyrazine compounds of formula (1), compositions including these compounds, and methods of their use are provided. Preferred compounds of formula 1 have activity as protein kinase inhibitors, including as inhibitors of c-MET.
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- Hydroboronation process
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The invention relates to processes for the synthesis of aryl or alkene borates which comprises reacting: (i) an olefinic compound having a halogen or halogen-like substituent in a vinylic substitution position, or (ii) an aromatic ring having a halogen or halogen-like substituent in a ring substitution position, with a disubstituted monohydroborane in the presence of a Group 8-11 metal catalyst. The invention also relates to the use of these borates in coupling reactions. The invention further relates to certain disubstituted monohydroboranes and aryl or alkene borates.
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Page column 69-70
(2010/02/05)
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