William F. Matter
Eli Lilly and Company
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Featured researches published by William F. Matter.
Biochemical and Biophysical Research Communications | 1992
William F. Matter; Raymond F. Brown; Chris J. Vlahos
Phosphatidylinositol (PtdIns) 3-kinase is an enzyme involved in cellular responses to growth factors. Quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyrano-4-one), a naturally occuring bioflavinoid, was found to inhibit PtdIns 3-kinase with an IC50 of 1.3 micrograms/ml (3.8 microM); inhibition appears to be directed towards the ATP binding site of the kinase. Analogs of quercetin were also investigated as PtdIns 3-kinase inhibitors, with the most potent compounds exhibiting IC50s in the range of 1.7-8.4 micrograms/ml (5-19 microM). In contrast, genistein, a potent tyrosine kinase inhibitor of the isoflavone class, did not inhibit PtdIns 3-kinase significantly (IC50 greater than 30 micrograms/ml). These findings suggest that flavinoids may serve as potent inhibitors of PtdIns 3-kinase. Furthermore, the enzyme is much more sensitive to substituents at the 3-position of the flavinoid ring than are other protein and PtdIns kinases, suggesting that specific inhibitors of PtdIns 3-kinase can be developed to explore the biological role of the enzyme in cellular proliferation and growth factor response.
FEBS Letters | 1992
Chris J. Vlahos; William F. Matter
Treatment of human neutrophils with the peptide f‐Met‐Leu‐Phe (FMLP) results in neutrophil activation concomitant with stimulation of phosphatidylinositol (PtdIns) 3‐kinase activity as measured by production of PtdIns‐3,4,5‐P3 in [32P]orthophosphate labeled cells. Antiphosphotyrosine immunoprecipitates were assayed for PtdIns 3‐kinase activity; essentially no activity was present in lysates from either stimulated or unstimulated cells. The 85 kDa regulatory subunit of PtdIns 3‐kinase, which normally serves as a substrate for tyrosine kinases, was not detected by SDS‐PAGE or Western blot analysis in antiphosphotyrosine immunoprecipitates. In addition, no radioactive band corresponding to PtdIns 3‐kinase was observed by SDS‐PAGE following antiPtdIns 3‐kinase immunoprecipitations. However, immunoprecipitates using polyclonal antibodies against PtdIns 3‐kinase showed high PtdIns 3‐kinase activity in neutrophil lysates and the 85kDa subunit of PtdIns 3‐kinase was detected in Western blots; no differences in activity were observed in FMLP‐stimulated and unstimulated cells. These results suggest that, in contrast to polypeptide growth factor signal transduction systems, the activation of PtdIns 3‐kinase by FMLP does not require tyrosine phosphorylation.
Journal of Biological Chemistry | 2005
Xushan Wang; Mary M. Mader; John E. Toth; Xiaohong Yu; Najia Jin; Robert M. Campbell; Jeffrey K. Smallwood; Michael E. Christe; Arindam Chatterjee; Theodore Goodson; Chris J. Vlahos; William F. Matter; Laura J. Bloem
Mixed lineage kinase 7 (MLK7) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the pro-apoptotic signaling pathways p38 and JNK. A library of potential kinase inhibitors was screened, and a series of dihydropyrrolopyrazole quinolines was identified as highly potent inhibitors of MLK7 in vitro catalytic activity. Of this series, an aryl-substituted dihydropyrrolopyrazole quinoline (DHP-2) demonstrated an IC50 of 70 nm for inhibition of pJNK formation in COS-7 cell MLK7/JNK co-transfection assays. In stimulated cells, DHP-2 at 200 nm or MLK7 small interfering RNA completely blocked anisomycin and UV induced but had no effect on interleukin-1β or tumor necrosis factor-α-induced p38 and JNK activation. Additionally, the compound blocked anisomycin and UV-induced apoptosis in COS-7 cells. Heart tissue homogenates from MLK7 transgenic mice treated with DHP-2 at 30 mg/kg had reduced JNK and p38 activation with no apparent effect on ERK activation, demonstrating that this compound can be used to block MLK7-driven MAPK pathway activation in vivo. Taken together, these data demonstrate that MLK7 is the MAPKKK required for modulation of the stress-activated MAPKs downstream of anisomycin and UV stimulation and that DHP-2 can be used to block MLK7 pathway activation in cells as well as in vivo.
ACS Medicinal Chemistry Letters | 2014
Prabhakar Kondaji Jadhav; Matthew A. Schiffler; Kostas Gavardinas; Euibong Jemes Kim; Donald P. Matthews; Michael A. Staszak; D. Scott Coffey; Bruce W. Shaw; Kenneth C. Cassidy; Richard A. Brier; Yuke Zhang; Robert M. Christie; William F. Matter; Keyun Qing; Jim D. Durbin; Yong Wang; Gary G. Deng
Cathepsin S (Cat S) plays an important role in many pathological conditions, including abdominal aortic aneurysm (AAA). Inhibition of Cat S may provide a new treatment for AAA. To date, several classes of Cat S inhibitors have been reported, many of which form covalent interactions with the active site Cys25. Herein, we report the discovery of a novel series of noncovalent inhibitors of Cat S through a medium-throughput focused cassette screen and the optimization of the resulting hits. Structure-based optimization efforts led to Cat S inhibitors such as 5 and 9 with greatly improved potency and drug disposition properties. This series of compounds binds to the S2 and S3 subsites without interacting with the active site Cys25. On the basis of in vitro potency, selectivity, and efficacy in a CaCl2-induced AAA in vivo model, 5 (LY3000328) was selected for clinical development.
Bioorganic & Medicinal Chemistry Letters | 1995
Jeffrey Alan Dodge; Henry U. Bryant; John Kim; William F. Matter; Bryan H. Norman; Usha Srinivasan; Chris J. Vlahos; Masahiko Sato
Abstract Structure-function studies on the natural product wortmannin have identified a 17β-hydroxy derivative as a potent inhibitor of osteoclast function in both cell and animal models. Mechanistic studies indicate osteoclast differentiation is dramatically affected by this class of compounds. Interestingly, comparable potency trends for resorption and phosphatidylinositol-3-kinase inhibition were also observed.
Journal of Biological Chemistry | 1994
Chris J. Vlahos; William F. Matter; K Y Hui; R F Brown
Cancer Research | 1994
Garth Powis; Rosanne Bonjouklian; Margareta M. Berggren; Alfred Gallegos; Robert Abraham; Curtis L. Ashendel; Leon H. Zalkow; William F. Matter; Jeffrey Alan Dodge; Gerald B. Grindey; Chris J. Vlahos
Biochemical and Biophysical Research Communications | 2001
William F. Matter; Thomas B. Estridge; Chen Zhang; Rama M. Belagaje; Louis Stancato; Jeff Dixon; Brian Johnson; Laura J. Bloem; Todd Pickard; Mary Donaghue; Susan Acton; Raju Jeyaseelan; Vivek J. Kadambi; Chris J. Vlahos
Analytical Biochemistry | 2005
Huaxian Chen; Joy L. Kovar; Sean Sissons; Karen L. Cox; William F. Matter; Fred Chadwell; Peng Luan; Chris J. Vlahos; Amy Schutz-Geschwender; D. Michael Olive
Blood | 2007
Jack L. Arbiser; Tweeny R. Kau; Martha Konar; Krishna K. Narra; Ramani Ramchandran; Scott A. Summers; Chris J. Vlahos; Keqiang Ye; Betsy N. Perry; William F. Matter; Anthony Fischl; James M. Cook; Pamela A. Silver; Jenny Bain; Philip Cohen; David Whitmire; Scott Furness; Baskaran Govindarajan; J. Phillip Bowen