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Maria A Argiriadi, Anna M Ericsson,
Christopher M Harris,
David L Banach,
David W Borhani,
David J Calderwood,
Megan D Demers,
Jennifer Dimauro,
Richard W Dixon,
Jennifer Hardman, [......],
Douglas Marcotte,
Kelly D Mullen,
Baofu Ni,
M Pietras,
Ramkrishna Sadhukhan,
Silvino Sousa,
Medha J Tomlinson,
Lu Wang,
Tao Xiang,
Robert V Talanian
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ABSTRACT: MK2 is a Ser/Thr kinase of significant interest as an anti-inflammatory drug discovery target. Here we describe the development of in vitro tools for the identification and characterization of MK2 inhibitors, including validation of inhibitor interactions with the crystallography construct and determination of the unique binding mode of 2,4-diaminopyrimidine inhibitors in the MK2 active site. Use of these tools in the optimization of a potent and selective inhibitor lead series is described in the accompanying Letter.
Bioorganic & medicinal chemistry letters 10/2009; 20(1):330-3. · 2.65 Impact Factor
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Christopher M Harris, Anna M Ericsson,
Maria A Argiriadi,
Claude Barberis,
David W Borhani,
Andrew Burchat,
David J Calderwood,
George A Cunha,
Richard W Dixon,
Kristine E Frank, [......],
Silvia Kwak,
Biqin Li,
Kelly D Mullen,
Denise C Perron,
Lu Wang,
Neil Wishart,
Xiaoyun Wu,
Xiaolei Zhang,
Tami R Zmetra,
Robert V Talanian
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ABSTRACT: We describe structure-based optimization of a series of novel 2,4-diaminopyrimidine MK2 inhibitors. Co-crystal structures (see accompanying Letter) demonstrated a unique inhibitor binding mode. Resulting inhibitors had IC(50) values as low as 19nM and moderate selectivity against a kinase panel. Compounds 15, 31a, and 31b inhibit TNFalpha production in peripheral human monocytes.
Bioorganic & medicinal chemistry letters 10/2009; 20(1):334-7. · 2.65 Impact Factor
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Jürgen Dinges,
Irini Akritopoulou-Zanze,
Lee D Arnold,
Teresa Barlozzari,
Peter F Bousquet,
George A Cunha, Anna M Ericsson,
Nobuhiko Iwasaki,
Michael R Michaelides,
Nobuo Ogawa,
Kathleen M Phelan,
Paul Rafferty,
Thomas J Sowin,
Kent D Stewart,
Ryukou Tokuyama,
Zhiren Xia,
Henry Q Zhang
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ABSTRACT: A series of 1,4-dihydroindeno[1,2-c]pyrazoles was prepared and evaluated for their enzymatic inhibition of KDR kinase. Computer modeling studies revealed the importance of attaching a basic side chain in predicting the binding mode of those compounds. Further investigation of structure-activity relationships led to 19, a lead compound with an acceptable selectivity profile, activity in whole cells, and good oral efficacy in an estradiol-induced murine uterine edema model of VEGF activity.
Bioorganic & Medicinal Chemistry Letters 09/2006; 16(16):4371-5. · 2.55 Impact Factor
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Kevin P Cusack,
Lee D Arnold,
Claude E Barberis,
Haipeng Chen, Anna M Ericsson,
Georgeen S Gaza-Bulseco,
Thomas D Gordon,
Christine M Grinnell,
Andreas Harsch,
Maria Pellegrini,
Edit Tarcsa
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ABSTRACT: Compounds that contain an alpha,beta-unsaturated carbonyl moiety are often flagged as potential Michael acceptors. All alpha,beta-unsaturated carbonyl moieties are not equivalent, however, and we sought to better understand this system and its potential implications in drug-like molecules. Measurement of the (13)C NMR shift of the beta-carbon and correlation to in vitro results allowed compounds in our collection to be categorized as potential Michael acceptors, potential substrates for NADPH, or as photoisomerizable.
Bioorganic & Medicinal Chemistry Letters 12/2004; 14(22):5503-7. · 2.55 Impact Factor
