- 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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Page/Page column 34; 166; 167
(2021/04/17)
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- Targeted Degradation of the Oncogenic Phosphatase SHP2
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SHP2 is a protein tyrosine phosphatase that plays a critical role in the full activation of the Ras-MAPK pathway upon stimulation of receptor tyrosine kinases, which are frequently amplified or mutationally activated in human cancer. In addition, activating mutations in SHP2 result in developmental disorders and hematologic malignancies. Several allosteric inhibitors have been developed for SHP2 and are currently in clinical trials. Here, we report the development and evaluation of a SHP2 PROTAC created by conjugating RMC-4550 with pomalidomide using a PEG linker. This molecule is highly selective for SHP2, induces degradation of SHP2 in leukemic cells at submicromolar concentrations, inhibits MAPK signaling, and suppresses cancer cell growth. SHP2 PROTACs serve as an alternative strategy for targeting ERK-dependent cancers and are useful tools alongside allosteric inhibitors for dissecting the mechanisms by which SHP2 exerts its oncogenic activity.
- Bae, Munhyung,Blacklow, Stephen C.,Cao, Ruili,Cuny, Gregory D.,Donovan, Katherine A.,Fischer, Eric S.,Henke, Matthew T.,Lumpkin, Ryan J.,Ray, Soumya S.,Rogers, Julia M.,Seegar, Tom C. M.,Vemulapalli, Vidyasiri
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p. 2593 - 2609
(2021/09/11)
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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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Page/Page column 32
(2019/11/04)
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- Calcilytic compounds
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Novel calcilytic compounds and methods of using them are provided.
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Page/Page column 14-15
(2016/01/25)
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- NEW THIENOPYRIMIDINE DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
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Compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R12, X, A and n are as defined in the description.
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Page/Page column 86
(2015/07/15)
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- MTH1 INHIBITORS FOR TREATMENT OF INFLAMMATORY AND AUTOIMMUNE CONDITIONS
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A compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of autoimmune diseases and inflammatory conditions.
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Page/Page column 61; 62
(2016/04/04)
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- INHIBITORS OF VIRAL REPLICATION
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The embodiments provide compounds of the general Formulas I-IV, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
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Page/Page column 50; 58
(2009/04/24)
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- ACRYLAMIDE DERIVATIVES AS VLA-1 INTEGRIN ANTAGONISTS AND USES THEREOF
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Compounds that are VLA-1 integrin antagonists are disclosed. Also disclosed are compositions containing such compounds, and methods of using such compounds in treating diseases mediated, at least in part, by the VLA-1 integrin.
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Page/Page column 323-324
(2010/02/10)
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- Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
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The present invention relates to novel cinnamide compounds that are useful for treating inflammatory and immunune diseases, to pharmaceutical compositions containing these compounds, and to methods of inhibiting inflammation or suppressing immune response in a mammal.
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- Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds
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The present invention relates to novel cinnamide compounds that are useful for treating inflammatory and immune diseases and cerebral vasospasm, to pharmaceutical compositions containing these compounds, and to methods of inhibiting inflammation or suppressing immune response in a mammal.
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- Integrating fragment assembly and biophysical methods in the chemical advancement of small-molecule antagonists of IL-2: An approach for inhibiting protein-protein interactions
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Fragment assembly has shown promise for discovering small-molecule antagonists for difficult targets, including protein-protein interactions. Here, we describe a process for identifying a 60 nM inhibitor of the interleukin-2 (IL-2)/IL-2 receptor (IL-2Rα)
- Raimundo, Brian C.,Oslob, Johan D.,Braisted, Andrew C.,Hyde, Jennifer,McDowell, Robert S.,Randal, Mike,Waal, Nathan D.,Wilkinson, Jennifer,Yu, Chul H.,Arkin, Michelle R.
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p. 3111 - 3130
(2007/10/03)
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- Discovery of a potent small molecule IL-2 inhibitor through fragment assembly
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Using a site-directed fragment discovery method called tethering, we have identified a 60 nM small molecule antagonist of a cytokine/receptor interaction (IL-2/IL2Rα) with cell-based activity. Starting with a low micromolar hit, we employed a combination
- Braisted, Andrew C.,Oslob, Johan D.,Delano, Warren L.,Hyde, Jennifer,McDowell, Robert S.,Waal, Nathan,Yu, Chul,Arkin, Michelle R.,Raimundo, Brian C.
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p. 3714 - 3715
(2007/10/03)
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