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Steven J Taylor,
Asitha Abeywardane,
Shuang Liang,
Ingo Muegge,
Anil K Padyana,
Zhaoming Xiong,
Melissa Hill-Drzewi,
Bennett Farmer,
Xiang Li,
Brandon Collins,
John Xiang Li,
Alexander Heim-Riether,
John Proudfoot,
Qiang Zhang,
Daniel Goldberg,
Ljiljana Zuvela-Jelaska,
Hani Zaher, Jun Li,
Neil A Farrow
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ABSTRACT: Matrix metalloproteases (MMPs) play an important role in cartilage homeostasis under both normal and inflamed disease states and, thus, have become attractive targets for the treatment of arthritic diseases. Herein, we describe the identification of a potent, selective MMP-13 inhibitor, developed using fragment-based structure-guided lead identification and optimization techniques. Virtual screening methods identified a novel, indole-based MMP-13 inhibitor that bound into the S1' pocket of the protein exhibiting a novel interaction pattern hitherto not observed in MMP-13 inhibitors. X-ray crystallographic structures were used to guide the elaboration of the fragment, ultimately leading to a potent inhibitor that was >100-fold selective over nine other MMP isoforms tested.
Journal of Medicinal Chemistry 12/2011; 54(23):8174-87. · 4.80 Impact Factor
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Donghong Amy Gao,
Zhaoming Xiong,
Alexander Heim-Riether,
Laura Amodeo,
E Michael August,
Xianhua Cao,
Leonard Ciccarelli,
Brandon K Collins,
Kyle Harrington,
Kathleen Haverty, [......],
Nelamangala Nagaraja,
John Proudfoot,
Rene Roman,
Sabine Schlyer,
Lana Smith Keenan,
Steven Taylor,
Bernd Wellenzohn,
Dieter Wiedenmayer, Jun Li,
Neil A Farrow
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ABSTRACT: SAR studies to improve the selectivity and metabolic stability of a class of recently discovered MMP-13 inhibitors are reported. Improved selectivity was achieved by modifying interactions with the S1' pocket. Metabolic stability was improved through reduction of inhibitor lipophilicity. This translated into lower in vivo clearance for the preferred compound.
Bioorganic & medicinal chemistry letters 09/2010; 20(17):5039-43. · 2.65 Impact Factor
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Jiang-Ping Wu,
Roman Fleck,
Janice Brickwood,
Alison Capolino,
Katrina Catron,
Zhidong Chen,
Charles Cywin,
Jonathan Emeigh,
Melissa Foerst,
John Ginn, [......],
Ian Potocki,
Michel Liuzzi,
Gregory W Peet,
Erika Scouten,
David Stefany,
Michael Turner,
Steve Weldon,
Clare Zimmitti,
Denise Spero,
Terence A Kelly
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ABSTRACT: An SAR study that identified a series of thienopyridine-based potent IkappaB Kinase beta (IKKbeta) inhibitors is described. With focuses on the structural optimization at C4 and C6 of structure 1 (Fig. 1), the study reveals that small alkyl and certain aromatic groups are preferred at C4, whereas polar groups with proper orientation at C6 efficiently enhance compound potency. The most potent analogues inhibit IKKbeta with IC50s as low as 40 nM, suppress LPS-induced TNF-alpha production in vitro and in vivo, display good kinase selectivity profiles, and are active in a HeLa cell NF-kappaB reporter gene assay, demonstrating that they directly interfere with the NF-kappaB signaling pathway.
Bioorganic & medicinal chemistry letters 09/2009; 19(19):5547-51. · 2.65 Impact Factor
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Alexander Heim-Riether,
Steven J Taylor,
Shuang Liang,
Donghong Amy Gao,
Zhaoming Xiong,
E Michael August,
Brandon K Collins,
Bennett T Farmer,
Kathleen Haverty,
Melissa Hill-Drzewi,
Hans-Dieter Junker,
S Mariana Margarit,
Neil Moss,
Thomas Neumann,
John R Proudfoot,
Lana Smith Keenan,
Renate Sekul,
Qiang Zhang, Jun Li,
Neil A Farrow
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ABSTRACT: Discovery and optimization of potency and selectivity of a non-Zn-chelating MMP-13 inhibitor with the aid of protein co-crystal structural information is reported. This inhibitor was observed to have a binding mode distinct from previously published MMP-13 inhibitors. Potency and selectivity were improved by extending the hit structure out from the active site into the S1' pocket.
Bioorganic & medicinal chemistry letters 09/2009; 19(18):5321-4. · 2.65 Impact Factor
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Kevin Qian,
Lian Wang,
Charles L. Cywin,
Bennett T. Farmer,
Eugene Hickey,
Carol Homon,
Scott Jakes,
Mohammed A. Kashem,
George Lee,
Scott Leonard, Jun Li,
Ronald Magboo,
Wang Mao,
Edward Pack,
Charlene Peng,
Anthony Prokopowicz,
Morgan Welzel,
John Wolak,
Tina Morwick
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ABSTRACT: A series of inhibitors of Pim-2 kinase identified by high-throughput screening is described. Details of the hit validation and lead generation process and structure−activity relationship (SAR) studies are presented. Disclosure of an unconventional binding mode for 1, as revealed by X-ray crystallography using the highly homologous Pim-1 protein, is also presented, and observed binding features are shown to correlate with the Pim-2 SAR. While highly selective within the kinase family, the series shows similar potency for both Pim-1 and Pim-2, which was expected on the basis of homology, but unusual in light of reports in the literature documenting a bias for Pim-1. A rationale for these observations based on Pim-1 and Pim-2 KM(ATP) values is suggested. Some interesting cross reactivity with casein kinase-2 was also identified, and structural features which may contribute to the association are discussed.
Journal of Medicinal Chemistry 04/2009; 52(7). · 4.80 Impact Factor
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ABSTRACT: The Pim family of Ser/Thr kinases has been implicated in the process of lymphomagenesis and cell survival. Known substrates of Pim kinases are few and poorly characterized. In this study we set out to identify novel Pim-2 substrates using the Kinase Substrate Tracking and Elucidation (KESTREL) approach. Two potential substrates, eukaryotic initiation factor 4B (eIF4B) and apoptosis inhibitor 5 (API-5), were identified from rat thymus extracts. Sequence comparison of the Pim-2 kinase phosphorylation sites of eIF4B and mouse BAD, the only other known Pim-2 substrate, revealed conserved amino acids preceding the phosphorylated serine residue. Stepwise replacement of the conserved residues produced a consensus sequence for Pim kinase recognition: RXRHXS. Pim-1 and Pim-2 catalyzed the phosphorylation of this recognition sequence 20-fold more efficiently than the original (K/R-K/R-R-K/R-L-S/T-a; a = small chain amino acid) Pim-1 phosphorylation site. The identification of the novel Pim kinase consensus sequence provides a more sensitive and versatile peptide based assay for screening modulators of Pim kinase activity.
Journal of Biochemistry 04/2007; 141(3):353-62. · 2.37 Impact Factor
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Kevin C Qian,
Lian Wang,
Eugene R Hickey,
Joey Studts,
Kevin Barringer,
Charline Peng,
Anthony Kronkaitis, Jun Li,
Andre White,
Sheenah Mische,
Bennett Farmer
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ABSTRACT: Pim-1 kinase is a member of a distinct class of serine/threonine kinases consisting of Pim-1, Pim-2, and Pim-3. Pim kinases are highly homologous to one another and share a unique consensus hinge region sequence, ER-PXPX, with its two proline residues separated by a non-conserved residue, but they (Pim kinases) have <30% sequence identity with other kinases. Pim-1 has been implicated in both cytokine-induced signal transduction and the development of lymphoid malignancies. We have determined the crystal structures of apo Pim-1 kinase and its AMP-PNP (5'-adenylyl-beta,gamma-imidodiphosphate) complex to 2.1-angstroms resolutions. The structures reveal the following. 1) The kinase adopts a constitutively active conformation, and extensive hydrophobic and hydrogen bond interactions between the activation loop and the catalytic loop might be the structural basis for maintaining such a conformation. 2) The hinge region has a novel architecture and hydrogen-bonding pattern, which not only expand the ATP pocket but also serve to establish unambiguously the alignment of the Pim-1 hinge region with that of other kinases. 3) The binding mode of AMP-PNP to Pim-1 kinase is unique and does not involve a critical hinge region hydrogen bond interaction. Analysis of the reported Pim-1 kinase-domain structures leads to a hypothesis as to how Pim kinase activity might be regulated in vivo.
Journal of Biological Chemistry 02/2005; 280(7):6130-7. · 4.77 Impact Factor
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Alexander Heim-Riether,
Steven J. Taylor,
Shuang Liang,
Donghong Amy Gao,
Zhaoming Xiong,
E. Michael August,
Brandon K. Collins,
Bennett T. Farmer II,
Kathleen Haverty,
Melissa Hill-Drzewi,
Hans-Dieter Junker,
S. Mariana Margarit,
Neil Moss,
Thomas Neumann,
John R. Proudfoot,
Lana Smith Keenan,
Renate Sekul,
Qiang Zhang, Jun Li,
Neil A. Farrow
Bioorganic & Medicinal Chemistry Letters. 19(18):5321-5324.
