- 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 166; 167
(2021/04/17)
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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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- Design and synthesis of novel triazolo-lapatinib hybrids as inhibitors of breast cancer cells
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A series of triazolo-lapatinib hybrids were synthesized via copper (II)-oxide nanoparticle (Cu2O-NP)-catalyzed azide-alkyne cycloaddition. The ability of these compounds to reduce the viability of breast cancer SKBR3 and SUM159 cells and stem cell-like KG-1a leukemia cells was subsequently evaluated. Compared with lapatinib, compounds 6c–f were more potent than lapatinib against the three cell lines. Next, the toxicity of compounds 6c–f was assessed in zebrafish. Compound 6d had comparable toxicity with lapatinib at 200 μM (mortality rate = 10 vs. 10%), and compound 6e had lower toxicity than lapatinib at 200 μM (mortality rate = 0 vs. 10%). Thus, compound 6e is a promising lead compound worthy of further investigation. [Figure not available: see fulltext.].
- Shi, YeHui,Zhang, Wei,Li, Lixin,Tong, ZhongSheng,Bai, CuiGai
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p. 2437 - 2445
(2018/11/10)
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- Identification of nonpeptidic small-molecule inhibitors of interleukin-2
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The identification, design, and synthesis of a series of novel sulfamide- and urea-based small-molecule antagonists of the protein-protein interaction IL-2/IL-2Rα are described. Installation of a furan carboxylic acid fragment onto a low-micromolar sulfamide resulted in a 23-fold improvement in activity, providing a sub-micromolar, nonpeptidic IL-2 inhibitor (IC 50 = 0.60 μM).
- Waal, Nathan D.,Yang, Wenjin,Oslob, Johan D.,Arkin, Michelle R.,Hyde, Jennifer,Lu, Wanli,McDowell, Robert S.,Yu, Chul H.,Raimundo, Brian C.
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p. 983 - 987
(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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