Browsing by Author "Zhang, Zhong-Yin"

Now showing 1 - 10 of 67
  • Thumbnail Image
    Item
    A facile hydroxyindole carboxylic acid based focused library approach for potent and selective inhibitors of Mycobacterium protein tyrosine phosphatase B
    (Wiley, 2013) Zeng, Li-Fan; Xu, Jie; He, Yantao; He, Rongjun; Wu, Li; Gunawan, Andrea M.; Zhang, Zhong-Yin; Biochemistry and Molecular Biology, School of Medicine
    Focused on Mtb: A facile hydroxyindole carboxylic acid based focused amide library was designed to target both the PTP active site and a unique nearby pocket for enhanced affinity and selectivity. HTS of the library led to the identification of a highly potent and selective inhibitor, 11 a, of mPTPB, an essential virulence factor for Mycobacterium tuberculosis. Compound 11 a shows high cellular activity and is capable of reversing the altered immune responses induced by mPTPB in macrophages.
  • Thumbnail Image
    Item
    A Highly Selective and Potent PTP-MEG2 Inhibitor with Therapeutic Potential for Type 2 Diabetes
    (ACS, 2012) Zhang, Sheng; Liu, Sijiu; Tao, Rongya; Wei, Dan; Chen, Lan; Shen, Weihua; Yu, Zhi-Hong; Wang, Lina; Jones, David R.; Dong, Xiaocheng C.; Zhang, Zhong-Yin; Biochemistry and Molecular Biology, School of Medicine
    Protein tyrosine phosphatases (PTPs) constitute a large family of signaling enzymes that control the cellular levels of protein tyrosine phosphorylation. A detailed understanding of PTP functions in normal physiology and in pathogenic conditions has been hampered by the absence of PTP-specific, cell-permeable small-molecule agents. We present a stepwise focused library approach that transforms a weak and general non-hydrolyzable pTyr mimetic (F(2)Pmp, phosphonodifluoromethyl phenylalanine) into a highly potent and selective inhibitor of PTP-MEG2, an antagonist of hepatic insulin signaling. The crystal structures of the PTP-MEG2-inhibitor complexes provide direct evidence that potent and selective PTP inhibitors can be obtained by introducing molecular diversity into the F(2)Pmp scaffold to engage both the active site and unique nearby peripheral binding pockets. Importantly, the PTP-MEG2 inhibitor possesses highly efficacious cellular activity and is capable of augmenting insulin signaling and improving insulin sensitivity and glucose homeostasis in diet-induced obese mice. The results indicate that F(2)Pmp can be converted into highly potent and selective PTP inhibitory agents with excellent in vivo efficacy. Given the general nature of the approach, this strategy should be applicable to other members of the PTP superfamily.
  • Thumbnail Image
    Item
    A novel micellular fluorogenic substrate for quantitating the activity of 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma (PLCγ) enzymes
    (Public Library of Science, 2024-03-29) Visvanathan, Ramya; Utsuki, Tadanobu; Beck, Daniel E.; Clayton, W. Brent; Lendy, Emma; Sun, Kuai-lin; Liu, Yinghui; Hering, Kirk W.; Mesecar, Andrew; Zhang, Zhong-Yin; Putt, Karson S.; Pharmacology and Toxicology, School of Medicine
    The activities of the phospholipase C gamma (PLCγ) 1 and 2 enzymes are essential for numerous cellular processes. Unsurprisingly, dysregulation of PLCγ1 or PLCγ2 activity is associated with multiple maladies including immune disorders, cancers, and neurodegenerative diseases. Therefore, the modulation of either of these two enzymes has been suggested as a therapeutic strategy to combat these diseases. To aid in the discovery of PLCγ family enzyme modulators that could be developed into therapeutic agents, we have synthesized a high-throughput screening-amenable micellular fluorogenic substrate called C16CF3-coumarin. Herein, the ability of PLCγ1 and PLCγ2 to enzymatically process C16CF3-coumarin was confirmed, the micellular assay conditions were optimized, and the kinetics of the reaction were determined. A proof-of-principle pilot screen of the Library of Pharmacologically Active Compounds 1280 (LOPAC1280) was performed. This new substrate allows for an additional screening methodology to identify modulators of the PLCγ family of enzymes.
  • Thumbnail Image
    Item
    A potent and selective small molecule inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases
    (ACS, 2013) He, Yantao; Liu, Sijiu; Menon, Ambili; Stanford, Stephanie; Oppong, Emmanuel; Gunawan, Andrea M.; Wu, Li; Wu, Dennis J.; Barrios, Amy M.; Bottini, Nunzio; Cato, Andrew C. B.; Zhang, Zhong-Yin; Biochemistry and Molecular Biology, School of Medicine
    Lymphoid-specific tyrosine phosphatase (LYP), a member of the protein tyrosine phosphatase (PTP) family of signaling enzymes, is associated with a broad spectrum of autoimmune diseases. Herein we describe our structure-based lead optimization efforts within a 6-hydroxy-benzofuran-5-carboxylic acid series culminating in the identification of compound 8b, a potent and selective inhibitor of LYP with a K(i) value of 110 nM and more than 9-fold selectivity over a large panel of PTPs. The structure of LYP in complex with 8b was obtained by X-ray crystallography, providing detailed information about the molecular recognition of small-molecule ligands binding LYP. Importantly, compound 8b possesses highly efficacious cellular activity in both T- and mast cells and is capable of blocking anaphylaxis in mice. Discovery of 8b establishes a starting point for the development of clinically useful LYP inhibitors for treating a wide range of autoimmune disorders.
  • Thumbnail Image
    Item
    Abnormal PTPN11 enhancer methylation promotes rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and joint inflammation
    (American Society for Clinical Investigation, 2016-05-19) Maeshima, Keisuke; Stanford, Stephanie M.; Hammaker, Deepa; Sacchetti, Cristiano; Zeng, Li-Fan; Ai, Rizi; Zhang, Vida; Boyle, David L.; Aleman Muench, German R.; Feng, Gen-Sheng; Whitaker, John W.; Zhang, Zhong-Yin; Wang, Wei; Bottini, Nunzio; Firestein, Gary S.; Department of Biochemistry & Molecular Biology, IU School of Medicine
    The PTPN11 gene, encoding the tyrosine phosphatase SHP-2, is overexpressed in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) compared with osteoarthritis (OA) FLS and promotes RA FLS invasiveness. Here, we explored the molecular basis for PTPN11 overexpression in RA FLS and the role of SHP-2 in RA pathogenesis. Using computational methods, we identified a putative enhancer in PTPN11 intron 1, which contained a glucocorticoid receptor- binding (GR-binding) motif. This region displayed enhancer function in RA FLS and contained 2 hypermethylation sites in RA compared with OA FLS. RA FLS stimulation with the glucocorticoid dexamethasone induced GR binding to the enhancer and PTPN11 expression. Glucocorticoid responsiveness of PTPN11 was significantly higher in RA FLS than OA FLS and required the differentially methylated CpGs for full enhancer function. SHP-2 expression was enriched in the RA synovial lining, and heterozygous Ptpn11 deletion in radioresistant or innate immune cells attenuated K/BxN serum transfer arthritis in mice. Treatment with SHP-2 inhibitor 11a-1 reduced RA FLS migration and responsiveness to TNF and IL-1β stimulation and reduced arthritis severity in mice. Our findings demonstrate how abnormal epigenetic regulation of a pathogenic gene determines FLS behavior and demonstrate that targeting SHP-2 or the SHP-2 pathway could be a therapeutic strategy for RA.
  • Thumbnail Image
    Item
    Access provided by IUPUI University Library, Indiana (Ruth Lilly) Altmetric: 0Citations: 2More detail Letter to the Editor Phosphatase PRL2 promotes AML1-ETO-induced acute myeloid leukemia
    (Nature, 2017) Kobayashi, Michihiro; Chen, Sisi; Bai, Yunpeng; Yao, Chonghua; Gao, Rui; Sun, Xiao-Jian; Mu, Chen; Twiggs, Taylor A.; Yu, Zhi-Hong; Boswell, H. Scott; Yoder, Mervin C.; Kapur, Reuben; Mulloy, James C.; Zhang, Zhong-Yin; Liu, Yan; Pediatrics, School of Medicine
  • Thumbnail Image
    Item
    Adapting AlphaLISA high throughput screen to discover a novel small-molecule inhibitor targeting protein arginine methyltransferase 5 in pancreatic and colorectal cancers
    (Impact Journals, 2017-05-23) Prabhu, Lakshmi; Wei, Han; Chen, Lan; Demir, Özlem; Sandusky, George; Sun, Emily; Wang, John; Mo, Jessica; Zeng, Lifan; Fishel, Melissa; Safa, Ahmad; Amaro, Rommie; Korc, Murray; Zhang, Zhong-Yin; Lu, Tao; Pharmacology and Toxicology, School of Medicine
    Pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC) are notoriously challenging for treatment. Hyperactive nuclear factor κB (NF-κB) is a common culprit in both cancers. Previously, we discovered that protein arginine methyltransferase 5 (PRMT5) methylated and activated NF-κB. Here, we show that PRMT5 is highly expressed in PDAC and CRC. Overexpression of PRMT5 promoted cancer progression, while shRNA knockdown showed an opposite effect. Using an innovative AlphaLISA high throughput screen, we discovered a lead compound, PR5-LL-CM01, which exhibited robust tumor inhibition effects in both cancers. An in silico structure prediction suggested that PR5-LL-CM01 inhibits PRMT5 by binding with its active pocket. Importantly, PR5-LL-CM01 showed higher anti-tumor efficacy than the commercial PRMT5 inhibitor, EPZ015666, in both PDAC and CRC. This study clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC, and establishes PR5-LL-CM01 as a promising basis for new drug development in the future.
  • Thumbnail Image
    Item
    Akt2 inhibits the activation of NFAT in lymphocytes by modulating calcium release from intracellular stores
    (Elsevier, 2012) Martin, Victoria A.; Wang, Wen-Horng; Lipchik, Andrew M.; Parker, Laurie L.; He, Yantao; Zhang, Sheng; Zhang, Zhong-Yin; Geahlen, Robert L.; Biochemistry and Molecular Biology, School of Medicine
    The engagement of antigen receptors on lymphocytes leads to the activation of phospholipase C-γ, the mobilization of intracellular calcium and the activation of the NFAT transcription factor. The coupling of antigen receptors to the activation of NFAT is modulated by numerous cellular effectors including phospho-inositide 3-kinase (PI3K), which is activated following receptor cross-linking. The activation of PI3K has both positive and negative effects on the receptor-mediated activation of NFAT. An increase in the level and activity of Akt2, a target of activated PI3K, potently inhibits the subsequent activation of NFAT. In contrast, an elevation in Akt1 has no effect on signaling. Signaling pathways operating both upstream and downstream of inositol 1,4,5-trisphosphate (IP3)-stimulated calcium release from intracellular stores are unaffected by Akt2. An increase in the level of Akt2 has no significant effect on the initial amplitude, but substantially reduces the duration of calcium mobilization. The ability of Akt2 to inhibit prolonged calcium mobilization is abrogated by the administration of a cell permeable peptide that blocks the interaction between Bcl-2 and the IP3 receptor. Thus, Akt2 is a negative regulator of NFAT activation through its ability to inhibit calcium mobilization from the ER.
  • Thumbnail Image
    Item
    Cefsulodin Inspired Potent and Selective Inhibitors of mPTPB, a Virulent Phosphatase from Mycobacterium tuberculosis
    (ACS Publications, 2015-12-10) He, Rongjun; Yu, Zhi-Hong; Zhang, Ruo-Yu; Wu, Li; Gunawan, Andrea M.; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    mPTPB is a virulent phosphatase from Mycobacterium tuberculosis and a promising therapeutic target for tuberculosis. To facilitate mPTPB-based drug discovery, we identified α-sulfophenylacetic amide (SPAA) from cefsulodin, a third generation β-lactam cephalosporin antibiotic, as a novel pTyr pharmacophore for mPTPB. Structure-guided and fragment-based optimization of SPAA led to the most potent and selective mPTPB inhibitor 9, with a K i of 7.9 nM and more than 10,000-fold preference for mPTPB over a large panel of 25 phosphatases. Compound 9 also exhibited excellent cellular activity and specificity in blocking mPTPB function in macrophage. Given its novel structure, modest molecular mass, and extremely high ligand efficiency (0.46), compound 9 represents an outstanding lead compound for anti-TB drug discovery targeting mPTPB.
  • Thumbnail Image
    Item
    CHEMICAL GENOMICS CORE FACILITY
    (Office of the Vice Chancellor for Research, 2015-04-17) Chen, Lan; Wu, Li; Gunawan, Andrea; Zhang, Zhong-Yin
    The Chemical Genomics Core Facility (CGCF) is a shared facility of the IU Simon Cancer Center and IU School of Medicine. The mission of CGCF is to provide excellence and innovation in high throughput screening (HTS) and medicinal chemistry. The core is fully equipped for automated high throughput screening and modern chemical synthesis. We have a series of state-of-art liquid handling robots, a variety of plate readers capable of measuring absorbance, fluorescence, fluorescence polarization, luminescence, time-resolved fluorescence and AlphaLISA. We have recently acquired a high content analysis (HCA or HCS) platform, which greatly enhanced our capability in image based cellular assays. Facility for chemical synthesis includes different HPLCs, LC-MS, NMR, flushing column systems, peptide synthesizer and microwave reactor. Our compound collection is about 230,000 including structurally diverse, pharmacophore-rich drug-like compounds, known drugs and bioactives, natural products and their derivatives. As the first core facility of its kind to be established in an academic setting in Indiana, we have a proven record of providing screening expertise and synthetic service to researchers across Indiana and beyond. This shared facility enables investigators to discover small molecule tools for basic research, therapeutic development and diagnostic applications. The CGCF has been designed to be highly flexible in order to meet the needs of multiple users employing a range of assays. Facility staff works closely with each investigator through all stages of the drug discovery process, providing an opportunity for students and fellows to gain experience and training in high throughput screening and medicinal chemistry at the facility.