Yuping Qiu
Bristol-Myers Squibb
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Publication
Featured researches published by Yuping Qiu.
Journal of Biological Chemistry | 2003
James R. Burke; Mark A. Pattoli; Kurt R. Gregor; Patrick J. Brassil; John F. MacMaster; Kim W. McIntyre; Xiaoxia Yang; Violetta Iotzova; Wendy Clarke; Joann Strnad; Yuping Qiu; F. Christopher Zusi
The signal-inducible phosphorylation of serines 32 and 36 of IκBα is critical in regulating the subsequent ubiquitination and proteolysis of IκBα, which then releases NF-κB to promote gene transcription. The multisubunit IκB kinase responsible for this phosphorylation contains two catalytic subunits, termed IκB kinase (IKK)-1 and IKK-2. BMS-345541 (4(2′-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline) was identified as a selective inhibitor of the catalytic subunits of IKK (IKK-2 IC50 = 0.3 μm, IKK-1 IC50 = 4 μm). The compound failed to inhibit a panel of 15 other kinases and selectively inhibited the stimulated phosphorylation of IκBα in cells (IC50 = 4 μm) while failing to affect c-Jun and STAT3 phosphorylation, as well as mitogen-activated protein kinase-activated protein kinase 2 activation in cells. Consistent with the role of IKK/NF-κB in the regulation of cytokine transcription, BMS-345541 inhibited lipopolysaccharide-stimulated tumor necrosis factor α, interleukin-1β, interleukin-8, and interleukin-6 in THP-1 cells with IC50 values in the 1- to 5-μmrange. Although a Dixon plot of the inhibition of IKK-2 by BMS-345541 showed a non-linear relationship indicating non-Michaelis-Menten kinetic binding, the use of multiple inhibition analyses indicated that BMS-345541 binds in a mutually exclusive manner with respect to a peptide inhibitor corresponding to amino acids 26–42 of IκBα with Ser-32 and Ser-36 changed to aspartates and in a non-mutually exclusive manner with respect to ADP. The opposite results were obtained when studying the binding to IKK-1. A binding model is proposed in which BMS-345541 binds to similar allosteric sites on IKK-1 and IKK-2, which then affects the active sites of the subunits differently. BMS-345541 was also shown to have excellent pharmacokinetics in mice, and peroral administration showed the compound to dose-dependently inhibit the production of serum tumor necrosis factor α following intraperitoneal challenge with lipopolysaccharide. Thus, the compound is effective against NF-κB activation in mice and represents an important tool for investigating the role of IKK in disease models.
Inflammation Research | 2003
John F. MacMaster; D. M. Dambach; D. B. Lee; K. K. Berry; Yuping Qiu; Fred Christopher Zusi; James R. Burke
AbstractObjective:Inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease are characterized by chronic relapsing inflammation. The transcription of many of the proteins which mediate the pathogenesis in inflammatory bowel disease (e.g., TNFα, ICAM-1, VCAM-1) is NF-κB-dependent. IκB kinase is critical in transducing the signal-inducible activation of NF-κB and, therefore, represents a potentially promising target for the development of novel agents to treat inflammatory bowel disease and other inflammatory diseases. Results:Here we show that BMS-345541, a highly selective inhibitor of IκB kinase, inhibited the TNFα-induced expression of both ICAM-1 and VCAM-1 in human umbilical vein endothelial cells at the same concentration range as cytokine expression is inhibited in monocytic cells (IC50 ≅ 5 μM). Against dextran sulfate sodium-induced colitis in mice, BMS-345541 administered orally at doses of 30 and 100 mg/kg was effective in blocking both clinical and histological endpoints of inflammation and injury. Conclusion:This represents the first example of an inhibitor of IκB kinase with anti-inflammatory activity in vivo and indicates that inhibitors of IkB kinase show the promise of being highly efficacious in inflammatory disorders such as inflammatory bowel disease.
Bioorganic & Medicinal Chemistry Letters | 2012
Denis R. St. Laurent; Makonen Belema; Min Gao; Jason Goodrich; Ramesh Kakarla; Jay O. Knipe; Julie A. Lemm; Mengping Liu; Omar D. Lopez; Van N. Nguyen; Peter T. Nower; Donald R. O’Boyle; Yuping Qiu; Jeffrey L. Romine; Michael H. Serrano-Wu; Jin-Hua Sun; Lourdes Valera; Fukang Yang; Xuejie Yang; Nicholas A. Meanwell; Lawrence B. Snyder
In a previous disclosure,(1) we reported the dimerization of an iminothiazolidinone to form 1, a contributor to the observed inhibition of HCV genotype 1b replicon activity. The dimer was isolated via bioassay-guided fractionation experiments and shown to be a potent inhibitor of genotype 1b HCV replication for which resistance mapped to the NS5A protein. The elements responsible for governing HCV inhibitory activity were successfully captured in the structurally simplified stilbene prolinamide 2. We describe herein the early SAR and profiling associated with stilbene prolinamides that culminated in the identification of analogs with PK properties sufficient to warrant continued commitment to this chemotype. These studies represent the key initial steps toward the discovery of daclatasvir (BMS-790052), a compound that has demonstrated clinical proof-of-concept for inhibiting the NS5A replication complex in the treatment of HCV infection.
Bioorganic & Medicinal Chemistry Letters | 2013
Omar D. Lopez; Van N. Nguyen; Denis R. St. Laurent; Makonen Belema; Michael H. Serrano-Wu; Jason Goodrich; Fukang Yang; Yuping Qiu; Amy Ripka; Peter T. Nower; Lourdes Valera; Mengping Liu; Donald R. O’Boyle; Jin-Hua Sun; Robert A. Fridell; Julie A. Lemm; Min Gao; Andrew C. Good; Nicholas A. Meanwell; Lawrence B. Snyder
In a recent disclosure, we described the discovery of dimeric, prolinamide-based NS5A replication complex inhibitors exhibiting excellent potency towards an HCV genotype 1b replicon. That disclosure dealt with the SAR exploration of the peripheral region of our lead chemotype, and herein is described the SAR uncovered from a complementary effort that focused on the central core region. From this effort, the contribution of the core region to the overall topology of the pharmacophore, primarily vector orientation and planarity, was determined, with a set of analogs exhibiting <10 nM EC(50) in a genotype 1b replicon assay.
Bioorganic & Medicinal Chemistry Letters | 2013
Makonen Belema; Van N. Nguyen; Denis R. St. Laurent; Omar D. Lopez; Yuping Qiu; Andrew C. Good; Peter T. Nower; Lourdes Valera; Donald R. O’Boyle; Jin-Hua Sun; Mengping Liu; Robert A. Fridell; Julie A. Lemm; Min Gao; Jay O. Knipe; Nicholas A. Meanwell; Lawrence B. Snyder
The isoquinolinamide series of HCV NS5A inhibitors exemplified by compounds 2b and 2c provided the first dual genotype-1a/1b (GT-1a/1b) inhibitor class that demonstrated a significant improvement in potency toward GT-1a replicons compared to that of the initial program lead, stilbene 2a. Structure-activity relationship (SAR) studies that uncovered an alternate phenylglycine-based cap series that exhibit further improvements in virology profile, along with some insights into the pharmacophoric elements associated with the GT-1a potency, are described.
Arthritis & Rheumatism | 2003
Kim W. McIntyre; David J. Shuster; Kathleen M. Gillooly; Donna M. Dambach; Mark A. Pattoli; Pin Lu; Xiadi Zhou; Yuping Qiu; F. Christopher Zusi; James R. Burke
Bioorganic & Medicinal Chemistry Letters | 2007
Francis Beaulieu; Carl Ouellet; Edward H. Ruediger; Makonen Belema; Yuping Qiu; Xuejie Yang; Jacques Banville; James R. Burke; Kurt R. Gregor; John F. MacMaster; Alain Martel; Kim W. McIntyre; Mark A. Pattoli; F. Christopher Zusi; Dolatrai M. Vyas
Bioorganic & Medicinal Chemistry Letters | 2007
Makonen Belema; Amy Bunker; Van N. Nguyen; Francis Beaulieu; Carl Ouellet; Yuping Qiu; Yunhui Zhang; Alain Martel; James R. Burke; Kim W. McIntyre; Mark A. Pattoli; Connie Daloisio; Kathleen M. Gillooly; Wendy Clarke; Patrick J. Brassil; F. Chris Zusi; Dolatrai M. Vyas
Archive | 2009
Makonen Belema; Andrew C. Good; Jason Goodrich; Ramesh Kakarla; Guo Li; Omar D. Lopez; Van N. Nguyen; Jayne Kapur; Yuping Qiu; Jeffrey L. Romine; R Laurent Denis; Michael H. Serrano-Wu; Lawrence B. Snyder; Fukang Yang
Archive | 2002
James R. Burke; Robert Townsend; Yuping Qiu; Fred Christopher Zusi; Steven G. Nadler