- Protein Modification at Tyrosine with Iminoxyl Radicals
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Post-translational modifications (PTMs) of proteins are a biological mechanism for reversibly controlling protein function. Synthetic protein modifications (SPMs) at specific canonical amino acids can mimic PTMs. However, reversible SPMs at hydrophobic amino acid residues in proteins are especially limited. Here, we report a tyrosine (Tyr)-selective SPM utilizing persistent iminoxyl radicals, which are readily generated from sterically hindered oximes via single-electron oxidation. The reactivity of iminoxyl radicals with Tyr was dependent on the steric and electronic demands of oximes; isopropyl methyl piperidinium oxime 1f formed stable adducts, whereas the reaction of tert-butyl methyl piperidinium oxime 1o was reversible. The difference in reversibility between 1f and 1o, differentiated only by one methyl group, is due to the stability of iminoxyl radicals, which is partly dictated by the bond dissociation energy of oxime O-H groups. The Tyr-selective modifications with 1f and 1o proceeded under physiologically relevant, mild conditions. Specifically, the stable Tyr-modification with 1f introduced functional small molecules, including an azobenzene photoswitch, to proteins. Moreover, masking critical Tyr residues by SPM with 1o, and subsequent deconjugation triggered by the treatment with a thiol, enabled on-demand control of protein functions. We applied this reversible Tyr modification with 1o to alter an enzymatic activity and the binding affinity of a monoclonal antibody with an antigen upon modification/deconjugation. The on-demand ON/OFF switch of protein functions through Tyr-selective and reversible covalent-bond formation will provide unique opportunities in biological research and therapeutics.
- Ishiyama, Takashi,Kanai, Motomu,Maruyama, Katsuya,Oisaki, Kounosuke,Sakai, Kentaro,Seki, Yohei,Togo, Takaya
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supporting information
p. 19844 - 19855
(2021/11/30)
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- N-(PYRIDIN-2-YLSULFONYL)CYCLOPROPANECARBOXAMIDE DERIVATIVES AND THEIR USE IN THE TREATMENT OF A CFTR MEDIATED DISEASE
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The invention relates to heterocyclic compounds of the formula (I), in which all of the variables are as defined in the specification; capable of modulating the activity of CFTR. The invention further provides a method for manufacturing compounds of the invention, and its therapeutic uses. The invention further provides methods to their preparation, to their medical use, in particular to their use in the treatment and management of diseases or disorders including Cystic fibrosis and related disorders.
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Page/Page column 192
(2020/07/14)
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- 2,5-DISUBSTITUTED 3-METHYL PYRAZINES AND 2,5,6-TRISUBSTITUTED 3-METHYL PYRAZINES AS ALLOSTERIC SHP2 INHIBITORS
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The present disclosure is directed to inhibitors of SHP2 and their use in the treatment of disease. Also disclosed are pharmaceutical compositions comprising the same.
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Paragraph 0400
(2018/03/26)
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- OXYMETHYLENE ARYL COMPOUNDS FOR TREATING INFLAMMATORY GASTROINTESTINAL DISEASES OR GASTROINTESTINAL CONDITIONS
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Use of oxymethylene aryl GPRl 19 agonists, and optionally DPP IV inhibitors and optionally metformin, for the treatment of inflammatory gastrointestinal diseases or gastrointestinal conditions involving malabsorption of nutrients and/or fluids are provide
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Paragraph 0409; 0410
(2018/03/28)
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- INDUCTION OF GATA2 BY HDAC1 AND HDAC2 INHIBITORS
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Provided herein are compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat diseases or disorders associated with Gata2 deficiency, particularly diseases or disorders that involve any type of HDAC1 and/or HDAC2 expression. Such diseases include acute myeloid leukemia (AML); familial myelodysplastic syndrome (MDS); leukemia; sickle-cell anemia; beta-thalassemia; monocytopenia and mycobacterial infections; dendritic cell, nonocyte, B, and natural killer lymphoid deficiency; Emberger syndrome; asymptomatic neurocognitive impairment; mild neurocognitive disorder; and HIV- associated dementia.
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Page/Page column 73; 74
(2016/05/02)
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- PIPERIDINE DERIVATIVES AS HDAC1/2 INHIBITORS
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Provided herein are compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat diseases or disorders associated with HDACl and/or HDAC2 activity.
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Page/Page column 34; 42
(2016/06/28)
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- BROMODOMAIN INHIBITORS AND USES THEREOF
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The present invention relates to compounds of formula (I): [INSERT FORMULA (1)] and to salts thereof, wherein R1, R2, Rc, and Rd have any of the values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of bromodomains. Also included are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and methods of using such compounds and salts in the treatment of various bromodomain-mediated disorders.
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Page/Page column 150
(2016/06/06)
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- PYRIMIDINE HYDROXY AMIDE COMPOUNDS AS HISTONE DEACETYLASE INHIBITORS
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Provided herein are compounds, pharmaceutical compositions comprising such compounds, and methods of using such compounds to treat or prevent diseases or disorders associated with HDAC activity, particularly diseases or disorders that involve activity of HDAC1, HDAC2, and/or HDAC6. Also provided herein are methods for inhibiting migration of a neuroblastoma cell, inducing maturation of a neuroblastoma cell, and altering cell cycle progression of a neuroblastoma cell comprising administering to the cell a therapeutically effective amount of a HDAC1, HDAC2, and/or HDAC6 selective inhibitor or a pharmaceutically acceptable salt thereof.
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Paragraph 0329; 0330
(2015/04/21)
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- BENZOXAZEPINES AS INHIBITORS OF P13K/MTOR AND METHODS OF THEIR USE AND MANUFACTURE
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The invention is directed to Compounds of Formula I: and pharmaceutically acceptable salts or solvates thereof, as well as methods of making and using the compounds. 9936396.1
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Page/Page column 165
(2012/06/15)
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- Pyrrolopyrazine Kinase Inhibitors
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The present invention relates to the use of novel pyrrolopyrazine derivatives of Formula I, wherein the variables n, p, q, Q, X, X′ and Y are defined as described herein, which inhibit JAK and SYK and are useful for the treatment of auto-immune and inflammatory diseases.
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Page/Page column 72
(2011/10/10)
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- AMINOBENZOQUINAZOLINONE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS
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The present invention is directed to aminobenzoquinazolinone compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds, and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor
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Page/Page column 49
(2011/08/03)
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- BENZOXAZEPINES AS INHIBITORS OF PI3K/m TOR AND METHODS OF THEIR USE AND MANUFACTURE
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The invention is directed to Compounds of Formula (I): the invention provides compounds that inhibit, regulate, and/or modulate P13K and/or mTOR that are useful in the treatment of hyperproliferative diseases, such as cancer, in mammals. This invention al
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Page/Page column 130-131
(2010/12/26)
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- BENZOXAZEPINES AS INHIBITORS OF MTOR AND METHODS OF THEIR USE AND MANUFACTURE
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The invention is directed to inhibitors of mTOR and pharmaceutically acceptable salts or solvates thereof, as well as methods of using them. The inhibitors are generally of structural formula wherein the combination of R1 and R2 are
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Page/Page column 32-33
(2010/12/26)
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- Non-aromatic A-ring replacement in the triaryl bis-sulfone CB2 receptor inhibitors
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The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inh
- Gilbert, Eric J.,Zhou, Guowei,Wong, Michael K.C.,Tong, Ling,Shankar, Bandarpalle B.,Huang, Chunli,Kelly, Joseph,Lavey, Brian J.,McCombie, Stuart W.,Chen, Lei,Rizvi, Razia,Dong, Youhao,Shu, Youheng,Kozlowski, Joseph A.,Shih, Neng-Yang,Hipkin, R. William,Gonsiorek, Waldemar,Malikzay, Asra,Lunn, Charles A.,Favreau, Len,Lundell, Daniel J.
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scheme or table
p. 608 - 611
(2010/05/02)
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- HETEROCYCLIC RECEPTOR AGONISTS FOR THE TREATMENT OF DIABETES AND METABOLIC DISORDERS
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Compounds and methods are provided for the treatment of, inter alia, Type II diabetes and other diseases associated with poor glycemic control. The compounds of the invention are orally active.
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Page/Page column 96-97
(2008/12/07)
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- CANNABINOID RECEPTOR LIGANDS
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There are disclosed compounds of the formula I: or a pharmaceutically acceptable salt of the compound, which exhibit anti-inflammatory and immunomodulatory activity. Also disclosed are pharmaceutical compositions containing said compounds.
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Page/Page column 51
(2010/02/05)
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