- SMALL MOLECULE MODULATORS OF GSK-3 ACTIVITY
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Compounds usable as substrate-competitive inhibitors of GSK-3, and uses thereof in modulating (e.g., inhibiting) GSK-3 activity and in treating biological conditions associated with GSK-3, are provided. The compounds can be collectively represented by Formula I, II or III, as described in the specification.
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- TARGETED BIFUNCTIONAL DEGRADERS
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The present invention provides, in one aspect, bifunctional compounds that can be used to promote or enhance degradation of certain circulating proteins. In another aspect, the present invention provides bifunctional compounds that can be used to promote or enhance degradation of certain autoantibodies. In certain embodiments, treatment or management of a disease and/or disorder requires degradation, removal, or reduction in concentration of the circulating protein or the autoantibody in the subject. Thus, in certain embodiments, administration of a compound of the invention to the subject removes or reduces the circulation concentration of the circulating protein or the autoantibody, thus treating, ameliorating, or preventing the disease and/or disorder. In certain embodiments, the circulating protein is TNF.
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- BIFUNCTIONAL SMALL MOLECULES TO TARGET THE SELECTIVE DEGRADATION OF CIRCULATING PROTEINS
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The present invention is directed to bifunctional small molecules which contain a circulating protein binding moiety (CPBM) linked through a linker group to a cellular receptor binding moiety (CRBM) which is a membrane receptor of degrading cell such as a hepatocyte or other degrading cell. In embodiments, the (CRBM) is a moiety which binds to asialoglycoprotein receptor (an asialoglycoprotein receptor binding moiety, or ASGPRBM) of a hepatocyte. In additional embodiments, the (CRBM) is a moiety which binds to a receptor of other cells which can degrade proteins, such as a LRP1, LDLR, FcyRI, FcRN, Transferrin or Macrophage Scavenger receptor. Pharmaceutical compositions based upon these bifunctional small molecules represent an additional aspect of the present invention. These compounds and/or compositions may be used to treat disease states and conditions by removing circulating proteins through degradation in the hepatocytes or macrophages of a patient or subject in need of therapy. Methods of treating disease states and/or conditions in which circulating proteins are associated with the disease state and/or condition are also described herein.
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- PROCESS OF PREPARING TYROSINE KINASE INHIBITOR
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The invention relates to a process for preparing sodium 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoate.
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- SMALL MOLECULE BASED ANTIBODY-RECRUITING COMPOUNDS FOR CANCER TREATMENT
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The present invention relates to chimeric (including bifunctional) compounds, compositions comprising those compounds and methods of treating cancer in a patient or subject, especially including metastatic cancer where cancer cells exhibit overexpression (heightened expression) of cell surface urokinase-type plasminogen activator receptor (urokinase receptor) compared to normal (non-cancerous) cells. The compounds bind to the urokinase-type plasminogen activator receptor (uPAR) on the surface of a cancer cell, including a metastatic cancer cell, and consequently recruit native antibodies of the patient or subject where the antibodies can selectively degrade and/or deactivate targeted cancer cells through antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity (ADCC) and/or complement dependent cytotoxicity (CDC) against a large number and variety of cancers, thus providing cancer cell death and an inhibition of growth, elaboration and/or metastasis of the cancer, including remission and cure of the patient's cancer.
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- Re-engineering the Immune Response to Metastatic Cancer: Antibody-Recruiting Small Molecules Targeting the Urokinase Receptor
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Developing selective strategies to treat metastatic cancers remains a significant challenge. Herein, we report the first antibody-recruiting small molecule (ARM) that is capable of recognizing the urokinase-type plasminogen activator receptor (uPAR), a uniquely overexpressed cancer cell-surface marker, and facilitating the immune-mediated destruction of cancer cells. A co-crystal structure of the ARM-U2/uPAR complex was obtained, representing the first crystal structure of uPAR complexed with a non-peptide ligand. Finally, we demonstrated that ARM-U2 substantially suppresses tumor growth in vivo with no evidence of weight loss, unlike the standard-of-care agent doxorubicin. This work underscores the promise of antibody-recruiting molecules as immunotherapeutics for treating cancer.
- Rullo, Anthony F.,Fitzgerald, Kelly J.,Muthusamy, Viswanathan,Liu, Min,Yuan, Cai,Huang, Mingdong,Kim, Minsup,Cho, Art E.,Spiegel, David A.
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p. 3642 - 3646
(2016/03/23)
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- Discovery, design and synthesis of 6H-anthra[1,9-cd]isoxazol-6-one scaffold as G9a inhibitor through a combination of shape-based virtual screening and structure-based molecular modification
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Protein lysine methyltransferase G9a is widely considered as an appealing antineoplastic target. Herein we present an integrated workflow combining shape-based virtual screening and structure-based molecular modification for the identification of novel G9a inhibitors. The shape-based similarity screening through ROCS overlay on the basis of the structure of UNC0638 was performed to identify CPUY074001 contained a 6H-anthra[1,9-cd]isoxazol-6-one scaffold as a hit. Analysis of the binding mode of CPUY074001 with G9a and 3D-QSAR results, two series compounds were designed and synthesized. The derivatives were confirmed to be active by in vitro assay and the SAR was explored by docking stimulations. Besides, several analogues showed acceptable anti-proliferative effects against several cancer cell lines. Among them, CPUY074020 displayed potent dual G9a inhibitory activity and anti-proliferative activity. Furthermore, CPUY074020 induced cell apoptosis in a dose-dependent manner and displayed a significant decrease in dimethylation of H3K9. Simultaneously, CPUY074020 showed reasonable in vivo PK properties. Altogether, our workflow supplied a high efficient strategy in the identification of novel G9a inhibitors. Compounds reported here can serve as promising leads for further study.
- Chen, Wei-Lin,Wang, Zhi-Hui,Feng, Tao-Tao,Li, Dong-Dong,Wang, Chu-Hui,Xu, Xiao-Li,Zhang, Xiao-Jin,You, Qi-Dong,Guo, Xiao-Ke
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p. 6102 - 6108
(2016/11/09)
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- COMPOSITIONS OF COMPOUNDS AND USES THEREOF
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The present disclosure relates to novel synthetic substituted heterocyclic compounds and pharmaceutical compositions containing the same. The disclosure further concerns the use of such compounds in the treatment and/or prevention of certain types of cancers, pain, inflammation, restenosis, atherosclerosis, psoriasis, thrombosis, Alzheimer's, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination.
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- CRYSTALLINE FORMS OF TRYOSINE KINASE INHIBITORS AND THEIR SALTS
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The invention relates to various polymorphic forms and amorphous form of sodium 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzate, including the polymorphic form A, mixtures of the polymorphs, process for the preparation thereof and the use thereof in a pharmaceutical composition containing thereof.
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- Small-molecule inhibition of the uPAR·uPA interaction: Synthesis, biochemical, cellular, in vivo pharmacokinetics and efficacy studies in breast cancer metastasis
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The uPAR·uPA protein-protein interaction (PPI) is involved in signaling and proteolytic events that promote tumor invasion and metastasis. A previous study had identified 4 (IPR-803) from computational screening of a commercial chemical library and shown that the compound inhibited uPAR·uPA PPI in competition biochemical assays and invasion cellular studies. Here, we synthesize 4 to evaluate in vivo pharmacokinetic (PK) and efficacy studies in a murine breast cancer metastasis model. First, we show, using fluorescence polarization and saturation transfer difference (STD) NMR, that 4 binds directly to uPAR with sub-micromolar affinity of 0.2 μM. We show that 4 blocks invasion of breast MDA-MB-231, and inhibits matrix metalloproteinase (MMP) breakdown of the extracellular matrix (ECM). Derivatives of 4 also inhibited MMP activity and blocked invasion in a concentration- dependent manner. Compound 4 also impaired MDA-MB-231 cell adhesion and migration. Extensive in vivo PK studies in NOD-SCID mice revealed a half-life of nearly 5 h and peak concentration of 5 μM. Similar levels of the inhibitor were detected in tumor tissue up to 10 h. Female NSG mice inoculated with highly malignant TMD-MDA-MB-231 in their mammary fat pads showed that 4 impaired metastasis to the lungs with only four of the treated mice showing severe or marked metastasis compared to ten for the untreated mice. Compound 4 is a promising template for the development of compounds with enhanced PK parameters and greater efficacy.
- Mani, Timmy,Wang, Fang,Knabe, William Eric,Sinn, Anthony L.,Khanna, May,Jo, Inha,Sandusky, George E.,Sledge Jr., George W.,Jones, David R.,Khanna, Rajesh,Pollok, Karen E.,Meroueh, Samy O.
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p. 2145 - 2155
(2013/05/09)
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- uPAR-uPA INTERACTION INHIBITORS AND METHODS FOR TREATING CANCER
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The invention described herein pertains to compounds, compositions and formulations comprising the compounds, and methods for use of the compounds, compositions and/or formulations in the treatment of diseases responsive to the inhibition of uPAR-uPA interactions, such as cancer.
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Page/Page column 40
(2012/09/21)
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- TRANSFORMATIONS OF 1-AZIDOANTHRAQUINONES AND ANTHRAISOXAZOL-6-ONES IN SULFURIC ACID
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When treated with sulfuric acid, 1-azido-4-bromoanthraquinones and 5-bromoanthraquinones and 5-bromoanthraisoxazol-6-ones are converted into 1-amino-4-hydroxyanthraquinones.The reaction is accompanied by the migration of bromine to position 2 or 3 of the final amine.
- Sakilidi, V. T.,Gornostaev, L. M.
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p. 939 - 942
(2007/10/02)
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