- Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction
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Aberrant activation of Wnt/β-catenin signaling is strongly associated with many diseases including cancer invasion and metastasis. Small-molecule targeting of the central signaling node of this pathway, β-catenin, is a biologically rational approach to abolish hyperactivation of β-catenin signaling but has been demonstrated to be a difficult task. Herein, we report a drug-like small molecule, ZW4864, that binds with β-catenin and selectively disrupts the protein-protein interaction (PPI) between B-cell lymphoma 9 (BCL9) and β-catenin while sparing the β-catenin/E-cadherin PPI. ZW4864 dose-dependently suppresses β-catenin signaling activation, downregulates oncogenic β-catenin target genes, and abrogates invasiveness of β-catenin-dependent cancer cells. More importantly, ZW4864 shows good pharmacokinetic properties and effectively suppresses β-catenin target gene expression in the patient-derived xenograft mouse model. This study offers a selective chemical probe to explore β-catenin-related biology and a drug-like small-molecule β-catenin/BCL9 disruptor for future drug development.
- Wang, Zhen,Zhang, Min,Quereda, Victor,Frydman, Sylvia M.,Ming, Qianqian,Luca, Vincent C.,Duckett, Derek R.,Ji, Haitao
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- Discovery of 2-(3-(3-Carbamoylpiperidin-1-yl)phenoxy)acetic Acid Derivatives as Novel Small-Molecule Inhibitors of the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction
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The β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/β-catenin signaling that is vigorously involved in cancer initiation and development. Herein, we describe the medicinal chemistry optimization of a screening hit to yield novel small-molecule inhibitors of the β-catenin/BCL9 interaction. The best compound 30 can disrupt the β-catenin/BCL9 interaction with a Ki of 3.6 μM in AlphaScreen competitive inhibition assays. Cell-based experiments revealed that 30 selectively disrupted the β-catenin/BCL9 PPI, while leaving the β-catenin/E-cadherin PPI unaffected, dose-dependently suppressed Wnt signaling transactivation, downregulated oncogenic Wnt target gene expression, and on-target selectively inhibited the growth of cancer cells harboring aberrant Wnt signaling. This compound with a new chemotype can serve as a lead compound for further optimization of inhibitors for β-catenin/BCL9 PPI.
- Wang, Zhen,Zhang, Min,Luo, Wen,Zhang, Yongqiang,Ji, Haitao
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- SMALL-MOLECULE INHIBITORS FOR THE Β-CATENIN/B-CELL LYMPHOMA 9 PROTEIN?PROTEIN INTERACTION
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Disclosed are inhibitors for the β-catenin/B-cell lymphoma 9 interaction. The inhibitors are selective for β-catenin/B-cell lymphoma 9 over β-catenin/ E-cadherin PPI interaction. Methods of using the disclosed compounds to treat cancer are also disclosed.
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Page/Page column 51; 144
(2021/04/01)
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- Propionic acid derivatives
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The present application relates to novel potent PPAR-alpha-activating compounds for treating, for example, coronary heart disease, and to their preparation.
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- HPPARS ACTIVATORS
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Compounds of formula (1) or a pharmaceutically acceptable salt, solvate, acid isostere, or hydrolyzable ester thereof, are disclosed. Methods of making and using the compounds are also disclosed. In particular methods for treating diseases or conditions a
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Page/Page column 21
(2010/02/07)
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- Identification of a series of PPARγ/δ dual agonists via solid-Phase parallel synthesis
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We have developed a general solid-phase synthesis for identification of PPAR ligands. Synthesis of a 480-member library led to the identification of a potent PPARγ/δ dual agonist 23. Compound 23 showed good plasma exposure in rats and demonstrated antihyp
- Liu, Kevin G,Lambert, Millard H,Leesnitzer, Lisa M,Oliver Jr., William,Ott, Ronda J,Plunket, Kelli D,Stuart, Ludwig W,Brown, Peter J,Willson, Timothy M,Sternbach, Daniel D
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p. 2959 - 2962
(2007/10/03)
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