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Steven Sheriff,
Brett R Beno,
Weixu Zhai,
Walter A Kostich,
Patricia A McDonnell,
Kevin Kish,
Valentina Goldfarb,
Mian Gao,
Susan E Kiefer,
Joseph Yanchunas,
Yanling Huang,
Shuhao Shi,
Shirong Zhu,
Carolyn Dzierba,
Joanne Bronson,
John E Macor,
Kingsley K Appiah,
Ryan S Westphal, Jonathan O'Connell,
Samuel W Gerritz
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ABSTRACT: Protein tyrosine phosphatases (PTPs) catalyze the dephosphorylation of tyrosine residues, a process that involves a conserved tryptophan-proline-aspartate (WPD) loop in catalysis. In previously determined structures of PTPs, the WPD-loop has been observed in either an "open" conformation or a "closed" conformation. In the current work, X-ray structures of the catalytic domain of receptor-like protein tyrosine phosphatase γ (RPTPγ) revealed a ligand-induced "superopen" conformation not previously reported for PTPs. In the superopen conformation, the ligand acts as an apparent competitive inhibitor and binds in a small hydrophobic pocket adjacent to, but distinct from, the active site. In the open and closed WPD-loop conformations of RPTPγ, the side chain of Trp1026 partially occupies this pocket. In the superopen conformation, Trp1026 is displaced allowing a 3,4-dichlorobenzyl substituent to occupy this site. The bound ligand prevents closure of the WPD-loop over the active site and disrupts the catalytic cycle of the enzyme.
Journal of Medicinal Chemistry 09/2011; 54(19):6548-62. · 4.80 Impact Factor
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Kingsley K Appiah,
Walter A Kostich,
Samuel W Gerritz,
Yanling Huang,
Brian D Hamman,
Jason Allen,
Wandong Zhang,
Thomas H Lanthorn,
Charles F Albright,
Ryan Westphal,
Martyn N Banks, Jonathan C O'Connell
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ABSTRACT: Protein tyrosine phosphatase-γ (PTP-γ) is a receptor-like PTP whose biological function is poorly understood. A recent mouse PTP-γ genetic deletion model associated the loss of PTP-γ gene expression with a potential antidepressant phenotype. This led the authors to screen a subset of the Bristol-Myers Squibb (BMS) compound collection to identify selective small-molecule inhibitors of receptor-like PTP-γ (RPTP-γ) for use in evaluating enzyme function in vivo. Here, they report the design of a high-throughput fluorescence resonance energy transfer (FRET) assay based on the Z'-LYTE technology to screen for inhibitors of RPTP-γ. A subset of the BMS diverse compound collection was screened and several compounds identified as RPTP-γ inhibitors in the assay. After chemical triage and clustering, compounds were assessed for potency and selectivity by IC(50) determination with RPTP-γ and two other phosphatases, PTP-1B and CD45. One hundred twenty-nine RPTP-γ selective (defined as IC(50) value greater than 5- to 10-fold over PTP-1B and CD45) inhibitors were identified and prioritized for evaluation. One of these hits, 3-(3, 4-dichlorobenzylthio) thiophene-2-carboxylic acid, was the primary chemotype for the initiation of a medicinal chemistry program.
Journal of Biomolecular Screening 03/2011; 16(5):476-85. · 2.05 Impact Factor
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Lalgudi S Harikrishnan,
Muthoni G Kamau,
Timothy F Herpin,
George C Morton,
Yalei Liu,
Christopher B Cooper,
Mark E Salvati,
Jennifer X Qiao,
Tammy C Wang,
Leonard P Adam, [......],
Alice Ye A Chen,
Xiaohong Yin,
Ramakrishna Seethala,
Tara L Peterson,
David S Nirschl,
Arthur V Miller,
Carolyn A Weigelt,
Kingsley K Appiah, Jonathan C O'Connell,
R Michael Lawrence
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ABSTRACT: 2-Arylbenzoxazole 5 was identified as a hit from a fluorescence-based high-throughput screen for CETP inhibitors. The synthesis and SAR investigation employing array synthesis of the A- and B-rings are described.
Bioorganic & medicinal chemistry letters 05/2008; 18(8):2640-4. · 2.65 Impact Factor
