- CONJUGATES OF AMPK INHIBITORS AND PROTAC DEGRADERS AND RELATED USES
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The present disclosure relates to compounds of Formula (I): T-L-D, stereoisomers thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof, wherein T is an AMPK inhibiting moiety; L is a linking moiety; and D is a PROTAC degrading moiety. The present disclosure also relates to uses of the compounds, e.g., to inhibit AMP-Activated protein kinase (AMPK), degrading AMPK protein, and/or treat cancer in a subject.
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Paragraph 0333; 0336
(2022/01/12)
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- DENDRIMER COMPOSITIONS AND METHODS FOR DRUG DELIVERY TO THE EYE
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Dendrimer compositions and methods for the treatment of one or more inflammatory and/or angiogenic diseases and/or disorders of the eye include hydroxyl-terminated dendrimers complexed or conjugated with one or more active agents for the treatment or alleviation of one or more symptoms of the diseases of the eye, and/or for diagnosing the diseases and/or disorders of the eye. The dendrimers may include one or more ethylene diamine-core poly(amidoamine) (PAMAM) hydroxyl-terminated generation-4, 5, 6, 7, 8, 9, or 10 dendrimers. The active agents may be VEGFR tyrosine kinase inhibitors including sunitinib or analogues thereof. Preferably, the compositions are suitable for administration via a systemic route to target activated microglia/macrophages in retina/choroid.
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- AMP-ACTIVATED PROTEIN KINASE INHIBITORS AND METHODS OF MAKING AND USING THE SAME
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The present disclosure relates to compounds of Formula (I): (I); stereoisomers thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof. The present disclosure also relates to uses of the compounds, e.g., to inhibit AMP-Activated protein kinase (AMPK) and treat cancer in a subject.
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Page/Page column 63-64
(2021/01/23)
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- Substituted oxindol-3-ylidenes as AMP-activated protein kinase (AMPK) inhibitors
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AMP-activated protein kinase (AMPK) is a central metabolic regulator that promotes cancer growth and survival under hypoxia and plays a role in the maintenance of cancer stem cells. A major challenge to interrogating the potential of targeting AMPK in cancer is the lack of potent and selective small molecule inhibitors. Compound C has been widely used as an AMPK inhibitor, but it lacks potency and has a poor selectivity profile. The multi-kinase inhibitor, sunitinib, has demonstrated potent nanomolar inhibition of AMPK activity and has scope for modification. Here, we have designed and synthesized several series of oxindoles to determine the structural requirements for AMPK inhibition and to improve selectivity. We identified two potent, novel oxindole-based AMPK inhibitors that were designed to interact with the DFG motif in the ATP-binding site of AMPK, this key feature evades interaction with the common recptor tyrosine kinase targets of sunitinib. Cellular engagement of AMPK by these oxindoles was confirmed by the inhibition of phosphorylation of acetyl-CoA carboxylase (ACC), a known substrate of AMPK, in myeloid leukemia cells. Interestingly, although AMPK is highly expressed and activated in K562 cells these oxindole-based AMPK inhibitors did not impact cell viability or result in significant cytotoxicity. Our studies serve as a platform for the further development of oxindole-based AMPK inhibitors with therapeutic potential.
- Backos, Donald S.,Casalvieri, Kimberly A.,Jordan, Craig T.,Matheson, Christopher J.,Minhajuddin, Mohammed,Reigan, Philip
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- Development of a novel conjugatable sunitinib analogue validated through in vitro and in vivo preclinical settings
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Sunitinib is an oral FDA/EMEA approved multi-targeted tyrosine kinase inhibitor. It possesses anti-angiogenic and antitumor activity against a variety of advanced solid tumors. However, its chemical core does not allow a potential linkage to tumor-homing elements that could eventually enhance its potency. Therefore, a novel linkable sunitinib derivative, designated SB1, was rationally designed and synthesized. The pharmaceutical profile of SB1 was explored both in vitro and in vivo. Mass spectrometry and NMR spectroscopy were utilized for characterization, while MTT assays and LC-MS/MS validated protocols were used to explore its antiproliferative effect and stability, respectively. Cytotoxicity evaluation in three glioma cells showed that SB1 preserved the antiproliferative effect of sunitinib. SB1 was stable in vitro after 24 h incubation in mouse plasma, while both agents exhibited bioequivalent pharmacokinetic characteristics after i.v. administration in Balb/c mice. To evaluate the levels of SB1 in mouse plasma, a novel analytical method was developed and validated in accordance to the US FDA and the EU EMA guidelines. We formulated a novel linkable sunitinib analog exhibiting similar antiproliferative and apoptotic properties with native sunitinib in glioma cell lines. Both SB1 and native sunitinib showed identical in vitro stability in mouse plasma and pharmacokinetics after i.v. administration in Balb/c mice.
- El Mubarak, Mohamed A.,Leontari, Iliana,Efstathia, Giannopoulou,Vrettos, Eirinaios I.,Shaikh, Abdul kadar,Konstantinos, Siatis E.,Danika, Charikleia,Kalofonos, Haralabos P.,Tzakos, Andreas G.,Sivolapenko, Gregory B.
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p. 515 - 523
(2018/07/06)
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- Synthesis of Novel c(AmpRGD)-Sunitinib Dual Conjugates as Molecular Tools Targeting the αvβ3 Integrin/VEGFR2 Couple and Impairing Tumor-Associated Angiogenesis
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On the basis of a previously discovered anti-αVβ3 integrin peptidomimetic (c(AmpRGD)) and the clinically approved antiangiogenic kinase inhibitor sunitinib, three novel dual conjugates were synthesized (compounds 1-3), featuring the covalent and robust linkage between these two active modules. In all conjugates, the ligand binding competence toward αVβ3 (using both isolated receptors and αVβ3-overexpressing endothelial progenitor EP cells) and the kinase inhibitory activity (toward both isolated kinases and EPCs) remained almost untouched and comparable to the activity of the single active units. Compounds 1-3 showed interesting antiangiogenesis properties in an in vitro tubulogenic assay; furthermore, dimeric-RGD conjugate 3 strongly inhibited in vivo angiogenesis in Matrigel plug assays in FVB mice. These results offer proof-of-concept of how the covalent conjugation of two angiogenesis-related small modules may result in novel and stable molecules, which impair tumor-related angiogenesis with equal or even superior ability as compared to the single modules or their simple combinations.
- Sartori, Andrea,Portioli, Elisabetta,Battistini, Lucia,Calorini, Lido,Pupi, Alberto,Vacondio, Federica,Arosio, Daniela,Bianchini, Francesca,Zanardi, Franca
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p. 248 - 262
(2017/04/26)
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- PROCESSES FOR THE PREPARATION OF 3-(PYRROL-2-YL)METHYLENE)-2-PYRROLONES USING 2-SILYLOXY-PYRROLES
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The present invention provides for synthetic processes for the making of substituted 3-((pyrrol-2-yl)methylene)-2-pyrrolones, including sunitinib. The present invention also provides for a process of crystallizing substantially pure sunitinib L-malate.
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Paragraph 0087
(2013/07/31)
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- PROCESSES FOR THE PREPARATION OF 3-(PYRROL-2-YL)METHYLENE)-2-PYRROLONES USING 2-SILYLOXY-PYRROLES
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The present invention provides for synthetic processes for the making of substituted 3-(Pyrrol-2-yl)methylene)-2-pyrrolones, including sunitinib. The present invention also provides for a process of crystallizing substantially pure sunitinib L-malate.
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Page/Page column 15; 22; 33
(2012/05/20)
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- A PROCESS FOR AMIDATION OF PYRROLE CARBOXYLATE COMPOUNDS
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The present invention relates to a process of amidation of pyrrole carboxylate compounds, including indolone-substituted pyrrole carboxylate compounds, characterized by using a cyclic alkyltriphosphonate anhydride coupling agent of formula (4) wherein A is C1-C6 alkyl group, preferably n-propyl group and to the use of the cyclic alkyltriphosphonate anhydride coupling agent of formula (4) in making pyrrole carboxamides.
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Page/Page column 15
(2011/10/05)
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- NOVEL PROCESS
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The present invention relates to novel intermediates and further to the use of said intermediates in processes for the preparation of indolinone derivatives, in particular 3- pyrrole substituted 2-indolinones having amide moieties on the pyrrole ring. Such compounds are useful in die treatment of abnormal cell growth, such as cancer, in mammals.
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Page/Page column 49-50
(2010/04/03)
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- DIHYDROINDOLE DERIVATIVES USEFUL IN PARKINSON'S DISEASE
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The invention relates to novel heterocyclic compounds of the formula (I) in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their use as medicaments and to medicaments comprising them.
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Page/Page column 15
(2009/04/25)
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- Kinase inhibitor compounds
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The invention relates to compounds, compositions comprising the compounds, and methods of using the compounds and compound compositions. The compounds, compositions, and methods described herein can be used for the therapeutic modulation of kinase-mediated processes, and treatment of disease and disease symptoms, particularly those mediated by certain kinase enzymes.
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Page/Page column 12; 13
(2009/04/24)
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- KINASE INHIBITOR COMPOUNDS
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The invention relates to compounds, compositions comprising the compounds, and methods of using the compounds and compound compositions. The compounds, compositions, and methods described herein can be used for the therapeutic modulation of kinase-mediated processes, and treatment of disease and disease symptoms, particularly those mediated by certain kinase enzymes.
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Page/Page column 34
(2008/06/13)
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- SUBSTITUTED 2-INDOLINONE AS PTK INHIBITORS CONTAINING A ZINC BINDING MOIETY
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The present invention relates to substituted 2-indolinone containing zinc- binding moiety based derivatives that have enhanced or unique properties as inhibitors of protein tyrosine kinase (PTK) receptors and their use in the treatment of PTK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 53; 57
(2008/06/13)
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- MULTI-FUNCTIONAL SMALL MOLECULES AS ANTI-PROLIFERATIVE AGENTS
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The present invention relates to the compositions, methods, and applications of a novel approach to selective inhibition of several cellular or molecular targets with a single small molecule. More specifically, the present invention relates to multi-functional small molecules wherein one functionality is capable of inhibiting histone deacetylases (HDAC) and the other functionality is capable of inhibiting a different cellular or molecular pathway involved in aberrant cell proliferation, differentiation or survival.
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Page/Page column 202
(2008/06/13)
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- AMINO ACID DERIVATIVES OF INDOLINONE BASED PROTEIN KINASE INHIBITORS
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Amino acid derivatives of pyrrolyl-indolinones and their amide or ester derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
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Page/Page column 6
(2008/06/13)
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- SOLID SALT FORMS OF A PYRROLE SUBSTITUTED 2-INDOLINONE
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The present invention relates to solid salt forms of the 3-pyrrole substituted 2-indolinone compound 5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pirrolidin-1-yl-ethyl)-amide. It also relates to polymorphs of the phosphate salt of the amide. The invention further relates to the use of the salts and polymorphs in the treatment of protein kinase related disorders.
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Page/Page column 17
(2008/06/13)
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- ENHANCED INDOLINONE BASED PROTEIN KINASE INHIBITORS
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Alpha-hydroxy- omega-(2-oxo-indolylidenemethyl-pyrrole-3'-carbonyl) amino alkanoic acid and amide derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein ki
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Page/Page column 10-11
(2010/11/25)
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- Treatment of excessive osteolysis with indolinone compounds
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Compounds of Formula I and Formula II, as described herein, are useful for treating excessive osteolysis, by inhibiting M-CSF mediated osteoclast development. The compounds also are useful for inhibiting phosphorylation of CSF1R, and for treating cancers that express CSF1R.
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- POLYMORPHS OF PYRROLE SUBSTITUTED 2-INDOLINONE PROTEIN KINASE INHIBITORS
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The present invention relates to polymorphs of the 3-pyrrole substituted 2-indolinone compound 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide.
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- Combination therapy for the treatment of cancer
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The present invention relates to methods for treatment or prevention of neoplasia disorders using protein tyrosine kinase inhibitors in combination with cyclooxygenase inhibitors, in particular cyclooxygenase-2 selective inhibitors.
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- Prodrugs of a 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives
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The present invention relates to pyrrole substituted 2-indolinone compounds and their pharmaceutically acceptable salts which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- Treatment of acute myeloid leukemia with indolinone compounds
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A method of treating acute myeloid leukemia in patient positive for FLT-3-ITD is described. The treatment is accomplished by administration of a compound of Formula I or II as defined herein.
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- 3-(4-amidopyrrol-2-ylmethylidene)-2-indolinone derivatives as portein kinase inhibitors
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The present invention relates to pyrrole substituted 2-indolinone compounds and their pharmaceutically acceptable salts which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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- Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase
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To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rβ tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.
- Sun, Li,Liang, Chris,Shirazian, Sheri,Zhou, Yong,Miller, Todd,Cui, Jean,Fukuda, Juri Y.,Chu, Ji-Yu,Nematalla, Asaad,Wang, Xueyan,Chen, Hui,Sistla, Anand,Luu, Tony C.,Tang, Flora,Wei, James,Tang, Cho
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p. 1116 - 1119
(2007/10/03)
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- Pyrrole substituted 2-indolinone protein kinase inhibitors
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The present invention relates to pyrrole substituted 2-indolinone compounds and their pharmaceutically acceptable salts which modulate the activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer.
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