Browsing by Author "Wu, Li"

Now showing 1 - 8 of 8
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    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.
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    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.
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    Diversity-Oriented Synthesis for Novel, Selective and Drug-like Inhibitors for a Phosphatase from Mycobacterium Tuberculosis
    (Royal Society of Chemistry, 2014-10) He, Rongjun; Bai, Yunpeng; Yu, Zhi-Hong; Wu, Li; Gunawan, Andrea Michelle; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Mycobacterium protein tyrosine phosphatase B (mPTPB) is a potential drug target of Tuberculosis (TB). Small molecule inhibitors of mPTPB could be a treatment to overcome emerging TB drug resistance. Using a Diversity-Oriented Synthesis (DOS) strategy, we successfully developed a salicylic acid based and drug-like mPTPB inhibitor with an IC50 of 2 μM and >20-fold specificity over many human PTPs, making it an excellent lead molecule for anti-TB drug discovery. In addition, DOS generated bicyclic salicylic acids are also promising starting points for acquiring inhibitors targeting other PTPs.
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    Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors
    (American Chemical Society, 2015-07-09) He, Rongjun; Yu, Zhi-Hong; Zhang, Ruo-Yu; Wu, Li; Gunawan, Andrea M.; Lane, Brandon S.; Shim, Joong S.; Zeng, Li-Fan; He, Yantao; Chen, Lan; Wells, Clark D.; Liu, Jun O.; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    Protein tyrosine phosphatases (PTPs) are potential therapeutic targets for many diseases. Unfortunately, despite considerable drug discovery efforts devoted to PTPs, obtaining selective and cell permeable PTP inhibitors remains highly challenging. We describe a strategy to explore the existing drug space for previously unknown PTP inhibitory activities. This led to the discovery of cefsulodin as an inhibitor of SHP2, an oncogenic phosphatase in the PTP family. Crystal structure analysis of SHP2 interaction with cefsulodin identified sulfophenyl acetic amide (SPAA) as a novel phosphotyrosine (pTyr) mimetic. A structure-guided and SPAA fragment-based focused library approach produced several potent and selective SHP2 inhibitors. Notably, these inhibitors blocked SHP2-mediated signaling events and proliferation in several cancer cell lines. Thus, SPAA may serve as a new platform for developing chemical probes for other PTPs.
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    Hydroxyindole carboxylic acid-based inhibitors for receptor-type protein tyrosine protein phosphatase beta
    (Mary Ann Liebert, Inc., 2014-05-10) Zeng, Li-Fan; Zhang, Ruo-Yu; Bai, Yunpeng; Wu, Li; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    AIMS: Protein tyrosine phosphatases (PTPs) play an important role in regulating a wide range of cellular processes. Understanding the role of PTPs within these processes has been hampered by a lack of potent and selective PTP inhibitors. Generating potent and selective probes for PTPs remains a significant challenge because of the highly conserved and positively charged PTP active site that also harbors a redox-sensitive Cys residue. RESULTS: We describe a facile method that uses an appropriate hydroxyindole carboxylic acid to anchor the inhibitor to the PTP active site and relies on the secondary binding elements introduced through an amide-focused library to enhance binding affinity for the target PTP and to impart selectivity against off-target phosphatases. Here, we disclose a novel series of hydroxyindole carboxylic acid-based inhibitors for receptor-type tyrosine protein phosphatase beta (RPTPβ), a potential target that is implicated in blood vessel development. The representative RPTPβ inhibitor 8b-1 (L87B44) has an IC50 of 0.38 μM and at least 14-fold selectivity for RPTPβ over a large panel of PTPs. Moreover, 8b-1 also exhibits excellent cellular activity and augments growth factor signaling in HEK293, MDA-MB-468, and human umbilical vein endothelial cells. INNOVATION: The bicyclic salicylic acid pharmacophore-based focused library approach may provide a potential solution to overcome the bioavailability issue that has plagued the PTP drug discovery field for many years. CONCLUSION: A novel method is described for the development of bioavailable PTP inhibitors that utilizes bicyclic salicylic acid to anchor the inhibitors to the active site and peripheral site interactions to enhance binding affinity and selectivity.
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    Molecular Basis of Gain-of-Function LEOPARD Syndrome-Associated SHP2 Mutations
    (American Chemical Society, 2014-07-01) Yu, Zhi-Hong; Zhang, Ruo-Yu; Walls, Chad D.; Chen, Lan; Zhang, Sheng; Wu, Li; Liu, Sijiu; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    The Src homology 2 (SH2) domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signal transducer downstream of growth factors that promotes the activation of the RAS-ERK1/2 cascade. In its basal state, SHP2 exists in an autoinhibited closed conformation because of an intramolecular interaction between its N-SH2 and protein tyrosine phosphatase (PTP) domains. Binding to pTyr ligands present on growth factor receptors and adaptor proteins with its N-SH2 domain localizes SHP2 to its substrates and frees the active site from allosteric inhibition. Germline mutations in SHP2 are known to cause both Noonan syndrome (NS) and LEOPARD syndrome (LS), two clinically similar autosomal dominant developmental disorders. NS-associated SHP2 mutants display elevated phosphatase activity, while LS-associated SHP2 mutants exhibit reduced catalytic activity. A conundrum in how clinically similar diseases result from mutations to SHP2 that have opposite effects on this enzyme’s catalytic functionality exists. Here we report a comprehensive investigation of the kinetic, structural, dynamic, and biochemical signaling properties of the wild type as well as all reported LS-associated SHP2 mutants. The results reveal that LS-causing mutations not only affect SHP2 phosphatase activity but also induce a weakening of the intramolecular interaction between the N-SH2 and PTP domains, leading to mutants that are more readily activated by competing pTyr ligands. Our data also indicate that the residual phosphatase activity associated with the LS SHP2 mutant is required for enhanced ERK1/2 activation. Consequently, catalytically impaired SHP2 mutants could display gain-of-function properties because of their ability to localize to the vicinity of substrates for longer periods of time, thereby affording the opportunity for prolonged substrate turnover and sustained RAS-ERK1/2 activation.
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    Structure-Based Design of Active-Site-Directed, Highly Potent, Selective, and Orally Bioavailable Low-Molecular-Weight Protein Tyrosine Phosphatase Inhibitors
    (American Chemical Society, 2022) He, Rongjun; Wang, Jifeng; Yu, Zhi-Hong; Moyers, Julie S.; Michael, M. Dodson; Durham, Timothy B.; Cramer, Jeff W.; Qian, Yuewei; Lin, Amy; Wu, Li; Noinaj, Nicholas; Barrett, David G.; Zhang, Zhong-Yin; Biochemistry and Molecular Biology, School of Medicine
    Protein tyrosine phosphatases constitute an important class of drug targets whose potential has been limited by the paucity of drug-like small-molecule inhibitors. We recently described a class of active-site-directed, moderately selective, and potent inhibitors of the low-molecular-weight protein tyrosine phosphatase (LMW-PTP). Here, we report our extensive structure-based design and optimization effort that afforded inhibitors with vastly improved potency and specificity. The leading compound inhibits LMW-PTP potently and selectively (Ki = 1.2 nM, >8000-fold selectivity). Many compounds exhibit favorable drug-like properties, such as low molecular weight, weak cytochrome P450 inhibition, high metabolic stability, moderate to high cell permeability (Papp > 0.2 nm/s), and moderate to good oral bioavailability (% F from 23 to 50% in mice), and therefore can be used as in vivo chemical probes to further dissect the complex biological as well as pathophysiological roles of LMW-PTP and for the development of therapeutics targeting LMW-PTP.
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    Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase
    (American Chemical Society, 2014-08-14) Zeng, Li-Fan; Zhang, Ruo-Yu; Yu, Zhi-Hong; Li, Sijiu; Wu, Li; Gunawan, Andrea M.; Lane, Brandon S.; Mali, Raghuveer S.; Li, Xingjun; Chan, Rebecca J.; Kapur, Reuben; Wells, Clark D.; Zhang, Zhong-Yin; Department of Biochemistry & Molecular Biology, IU School of Medicine
    , The Src homology 2 domain containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase associated with various kinds of leukemia and solid tumors. Thus, there is substantial interest in developing SHP2 inhibitors as potential anticancer and antileukemia agents. Using a structure-guided and fragment-based library approach, we identified a novel hydroxyindole carboxylic acid-based SHP2 inhibitor 11a-1, with an IC50 value of 200 nM and greater than 5-fold selectivity against 20 mammalian PTPs. Structural and modeling studies reveal that the hydroxyindole carboxylic acid anchors the inhibitor to the SHP2 active site, while interactions of the oxalamide linker and the phenylthiophene tail with residues in the β5–β6 loop contribute to 11a-1’s binding potency and selectivity. Evidence suggests that 11a-1 specifically attenuates the SHP2-dependent signaling inside the cell. Moreover, 11a-1 blocks growth factor mediated Erk1/2 and Akt activation and exhibits excellent antiproliferative activity in lung cancer and breast cancer as well as leukemia cell lines.