- TREATMENT OF FIBROSIS WITH IRE1 SMALL MOLECULE INHIBITORS
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Provided herein are methods of using IRE1 small molecule inhibitors in combination therapies for treating fibrosis in a subject. The IRE1 small molecule inhibitors described herein may be used in combination therapies for treating fibrosis
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Paragraph 00199
(2020/11/30)
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- IRE1 SMALL MOLECULE INHIBITORS
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Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a
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Paragraph 00151
(2020/07/06)
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- COMBINATION THERAPIES WITH IRE1 SMALL MOLECULE INHIBITORS
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Provided herein are methods of using IRE1 small molecule inhibitors in combination therapies for treating cancer in a subject. The IRE1 small molecule inhibitors described herein may be used in combination therapies for treating solid and hematologic cancers.
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Paragraph 00223
(2020/12/01)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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Heterocyclic compounds as Wee1 inhibitors are provided. The compounds may find use as therapeutic agents for the treatment of diseases and may find particular use in oncology.
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Paragraph 0960-0962
(2019/04/25)
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- IRE1 SMALL MOLECULE INHIBITORS
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Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a subject. Moreover, IRE1 small molecule inhibitors described herein are for the treatment of cancer, where the cancer is a solid or hematologic cancer.
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Paragraph 00259
(2019/05/30)
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- IRE1 SMALL MOLECULE INHIBITORS
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Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a
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Paragraph 00260
(2018/06/22)
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- IRE1 SMALL MOLECULE INHIBITORS
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Provided herein are small molecule inhibitors for the targeting or IRE1 protein family members. Binding may be direct or indirect. Further provided herein are methods of using IRE1 small molecule inhibitors for use in treating or ameliorating cancer in a subject. Moreover, IRE1 small molecule inhibitors described herein are for the treatment of cancer, where the cancer is a solid or hematologic cancer.
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Paragraph 00175
(2019/01/05)
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- Design, Synthesis, and Pharmacological Evaluation of Novel Multisubstituted Pyridin-3-amine Derivatives as Multitargeted Protein Kinase Inhibitors for the Treatment of Non-Small Cell Lung Cancer
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A novel series of pyridin-3-amine derivatives were designed, synthesized, and evaluated as multitargeted protein kinase inhibitors for the treatment of non-small cell lung cancer (NSCLC). Hit 1 was first disclosed by in silico screening against fibroblast
- Zhu, Wei,Chen, Hui,Wang, Yulan,Wang, Jiang,Peng, Xia,Chen, Xianjie,Gao, Yinglei,Li, Chunpu,He, Yulong,Ai, Jing,Geng, Meiyu,Zheng, Mingyue,Liu, Hong
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p. 6018 - 6035
(2017/08/02)
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- FUSED AMINODIHYDROPYRIMIDINE DERIVATIVE
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The present invention provides, for example, the following compound: wherein ring A is a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle, X1—X2═X3 is CR5—CR6═CRs
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Paragraph 0200; 0201
(2013/08/28)
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- Maximizing lipophilic efficiency: The use of Free-Wilson analysis in the design of inhibitors of acetyl-CoA carboxylase
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This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.
- Freeman-Cook, Kevin D.,Amor, Paul,Bader, Scott,Buzon, Leanne M.,Coffey, Steven B.,Corbett, Jeffrey W.,Dirico, Kenneth J.,Doran, Shawn D.,Elliott, Richard L.,Esler, William,Guzman-Perez, Angel,Henegar, Kevin E.,Houser, Janet A.,Jones, Christopher S.,Limberakis, Chris,Loomis, Katherine,McPherson, Kirk,Murdande, Sharad,Nelson, Kendra L.,Phillion, Dennis,Pierce, Betsy S.,Song, Wei,Sugarman, Eliot,Tapley, Susan,Tu, Meihua,Zhao, Zhengrong
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supporting information; experimental part
p. 935 - 942
(2012/03/11)
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- 2-Aminothiadiazole inhibitors of AKT1 as potential cancer therapeutics
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A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.
- Zeng, Qingping,Bourbeau, Matthew P.,Wohlhieter, G. Erich,Yao, Guomin,Monenschein, Holger,Rider, James T.,Lee, Matthew R.,Zhang, Shiwen,Lofgren, Julie,Freeman, Daniel,Li, Chun,Tominey, Elizabeth,Huang, Xin,Hoffman, Douglas,Yamane, Harvey,Tasker, Andrew S.,Dominguez, Celia,Viswanadhan, Vellarkad N.,Hungate, Randall,Zhang, Xiaoling
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scheme or table
p. 1652 - 1656
(2010/07/15)
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- PYRAZOLOSPIROKETONE ACETYL-C0A CARBOXYLASE INHIBITORS
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The invention provides compounds of Formula (1) or a pharmaceutically acceptable salt of said compound, wherein R1, R2, and R3 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of acetyl-CoA carboxylase enzyme(s) in an animal.
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Page/Page column 43
(2009/12/27)
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- HETEROCYCLIC MODULATORS OF PKB
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The invention relates to heterocyclic compounds of Formula I and compositions thereof useful for treating diseases mediated by protein kinase B (PKB) where the variables have the definitions provided herein Formula (I). The invention also relates to the therapeutic use of such compounds and compositions thereof in treating disease states associated with abnormal cell growth, cancer, inflammation, and metabolic disorders.
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Page/Page column 95
(2009/03/07)
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- Amino-substituted heterocycles, compositions thereof, and methods of treatment therewith
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Provided herein are Heterocyclic Compounds having the following structure: wherein R1, R2, X, Y and Z are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound and methods for treating or preventing cancer, inflammatory conditions, immunological conditions, metabolic conditions and conditions treatable or preventable by inhibition of a kinase pathway comprising administering an effective amount of a Heterocyclic Compound to a patient in need thereof.
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Page/Page column 41
(2008/12/07)
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- KINASE INHIBITORS
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Disclosed is a compound of the formula (I) and the pharmaceutically acceptable salts thereof. Also disclosed are methods of treating protein kinase mediatied diseases using the compound of formula 1.0. Also disclosed are methods of treating cancer using a
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Page/Page column 89
(2008/06/13)
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- Synthesis and SAR of indazole-pyridine based protein kinase B/Akt inhibitors
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A series of heteroaryl-pyridine containing inhibitors of Akt are reported. The synthesis and structure-activity relationships are discussed, leading to the discovery of a indazole-pyridine analogue (Ki = 0.16 nM). These compounds bind in the ATP binding site, are potent, ATP competitive, and reversible inhibitors of Akt activity. No selectivity amongst the Akt isoforms is observed for this analogue, but there is good selectivity against an panel of other kinases. It is least selective for other members of the AGC family of kinases but is nonetheless 40-fold selective for Akt over PKA. The compound shows cellular activity and significantly slows tumor growth in vivo.
- Woods, Keith W.,Fischer, John P.,Claiborne, Akiyo,Li, Tongmei,Thomas, Sheela A.,Zhu, Gui-Dong,Diebold, Robert B.,Liu, Xuesong,Shi, Yan,Klinghofer, Vered,Han, Edward K.,Guan, Ran,Magnone, Shayna R.,Johnson, Eric F.,Bouska, Jennifer J.,Olson, Amanda M.,Jong, Ron de,Oltersdorf, Tilman,Luo, Yan,Rosenberg, Saul H.,Giranda, Vincent L.,Li, Qun
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p. 6832 - 6846
(2007/10/03)
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- THIADIAZOLE COMPOUNDS AND METHODS OF USE
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The invention relates to thiadiazole compounds useful for treating diseases mediated by protein kinase B (PKB). The invention also relates to the therapeutic use of such thiadiazole compounds and compositions thereof in treating disease states associated
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Page/Page column 23
(2010/11/08)
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- Aminopyrazine analogs for treating glaucoma and other rho kinase-mediated diseases and conditions
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Methods for using aminopyrazine analogs to treat rho kinase-mediated diseases or rho kinase-mediated conditions, including controlling intraocular pressure and treating glaucoma, are disclosed. Ophthalmic pharmaceutical compositions useful in the treatment of eye diseases such as glaucoma, and additionally useful for controlling intraocular pressure, the compositions comprising an effective amount of aminopyrazine analogs, are also disclosed.
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Page/Page column 24
(2008/06/13)
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- KINASE INHIBITORS
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A compound having the general structure of Formula (I) or a pharmaceutically acceptable salt, solvate, or ester thereof, are useful in treating diseases, disorders, or conditions such as immunodeficiencies, cancers, cardiovascular diseases, endocrine disorders, Parkinson's disease, metabolic diseases, tumorigenesis, Alzheimer's disease, heart disease, diabetes, neurodegeneration, inflammation, kidney disease, atherosclerosis and airway disease.
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Page/Page column 68-69
(2008/06/13)
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- Kinase inhibitors
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Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are compositions which inhibit protein kinases and methods of inhibiting protein kinases in a patient.
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Page/Page column 38
(2010/01/31)
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