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ABSTRACT: Herein we describe the identification and characterization of a class of molecules that are believed to extend into a region of p38 known as the 'switch pocket'. Although these molecules lack a canonical hinge binding motif, they show K(i) values as low as 100 nM against p38. We show that molecules that interact with this region of the protein demonstrate different binding kinetics than a canonical ATP mimetic, as well as a wide range of kinome profiles. Thus, the switch pocket presents new opportunities for kinome selectivity which could result in unique biochemical responses and offer new opportunities in the field of kinase drug discovery.
Bioorganic & medicinal chemistry letters 10/2010; 20(19):5787-92. · 2.65 Impact Factor
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Derek W Nelson, Kathy Sarris,
Douglas M Kalvin,
Marian T Namovic,
George Grayson,
Diana L Donnelly-Roberts,
Richard Harris,
Prisca Honore,
Michael F Jarvis,
Connie R Faltynek,
William A Carroll
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ABSTRACT: N'-aryl acyl hydrazides were identified as P2X7 receptor antagonists. Structure-activity relationship (SAR) studies evaluated functional activity by monitoring calcium flux inhibition in cell lines expressing recombinant human and rat P2X7 receptors. Selected analogs were assayed in vitro for their capacity to inhibit release of cytokine IL-1beta. Compounds with potent antagonist function were evaluated in vivo using the zymosan-induced peritonitis model. A representative compound effectively attenuated mechanical allodynia in a rat model of neuropathic pain.
Journal of Medicinal Chemistry 06/2008; 51(10):3030-4. · 5.25 Impact Factor
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Michael D Wendt,
Chaohong Sun,
Aaron Kunzer,
Daryl Sauer, Kathy Sarris,
Ethan Hoff,
Liping Yu,
David G Nettesheim,
Jun Chen,
Sha Jin,
Kenneth M Comess,
Yihong Fan,
Steven N Anderson,
Binumol Isaac,
Edward T Olejniczak,
Philip J Hajduk,
Saul H Rosenberg,
Steven W Elmore
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ABSTRACT: Survivin is one of the most tumor-specific genes in the human genome and is an attractive target for cancer therapy. However, small-molecule ligands for survivin have not yet been described. Thus, an interrogation of survivin which could potentially both validate a small-molecule therapy approach, and determine the biochemical nature of any of survivin's functions has not been possible. Here we describe the discovery and characterization of a small molecule binding site on the survivin surface distinct from the Smac peptide-binding site. The new site is located at the dimer interface and exhibits many of the features of highly druggable, biologically relevant protein binding sites. A variety of small hydrophobic compounds were found that bind with moderate affinity to this binding site, from which one lead was developed into a group of compounds with nanomolar affinity. Additionally, a subset of these compounds are adequately water-soluble and cell-permeable. Thus, the structural studies and small molecules described here provide tools that can be used to probe the biochemical role(s) of survivin, and may ultimately serve as a basis for the development of small molecule therapeutics acting via direct or allosteric disruption of binding events related to this poorly understood target.
Bioorganic & Medicinal Chemistry Letters 06/2007; 17(11):3122-9. · 2.55 Impact Factor
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Kathleen H Mortell,
David J Anderson,
James J Lynch,
Sherry L Nelson, Kathy Sarris,
Heath McDonald,
Reza Sabet,
Scott Baker,
Prisca Honore,
Chih-Hung Lee,
Michael F Jarvis,
Murali Gopalakrishnan
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ABSTRACT: A series of alpha-amino acids were identified as ligands which compete with gabapentin for binding to the alpha(2)delta subunit of voltage-dependent Ca(2+) channels. Potent analogs were identified. Their activity in an in vivo pain assay is described.
Bioorganic & Medicinal Chemistry Letters 04/2006; 16(5):1138-41. · 2.55 Impact Factor
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ABSTRACT: We report the synthesis of kinase targeted libraries based on the thienopyrazole scaffold. Several thienopyrazole analogs have been identified as submicromolar inhibitors of KDR.
Bioorganic & Medicinal Chemistry Letters 02/2006; 16(1):96-9. · 2.55 Impact Factor
