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Your search keyword '"Smith, Donna-Michelle"' showing total 3 results
Start Over Author "Smith, Donna-Michelle" Publisher american chemical society
3 results on '"Smith, Donna-Michelle"'

1. Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.

Author

Woodhead AJ, Angove H, Carr MG, Chessari G, Congreve M, Coyle JE, Cosme J, Graham B, Day PJ, Downham R, Fazal L, Feltell R, Figueroa E, Frederickson M, Lewis J, McMenamin R, Murray CW, O'Brien MA, Parra L, Patel S, Phillips T, Rees DC, Rich S, Smith DM, Trewartha G, Vinkovic M, Williams B, and Woolford AJ

Subjects
Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Benzamides pharmacokinetics, Benzamides pharmacology, Cell Line, Crystallography, X-Ray, Drug Design, Drug Screening Assays, Antitumor, Drug Stability, Female, HCT116 Cells, HSP90 Heat-Shock Proteins chemistry, Humans, Isoindoles pharmacokinetics, Isoindoles pharmacology, Ligands, Mice, Mice, Inbred BALB C, Mice, Nude, Models, Molecular, Molecular Conformation, Neoplasm Transplantation, Solubility, Structure-Activity Relationship, Tissue Distribution, Transplantation, Heterologous, Antineoplastic Agents chemical synthesis, Benzamides chemical synthesis, HSP90 Heat-Shock Proteins antagonists & inhibitors, Isoindoles chemical synthesis
Abstract

Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.

Published
2010
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2. Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design.

Author

Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Reule M, Saxty G, Seavers LC, Smith DM, Squires MS, Trewartha G, Walker MT, and Woolford AJ

Subjects
Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Colonic Neoplasms drug therapy, Crystallography, X-Ray, Drug Design, Enzyme Inhibitors pharmacokinetics, Enzyme Inhibitors therapeutic use, Humans, Mice, Piperidines pharmacokinetics, Piperidines therapeutic use, Pyrazoles pharmacokinetics, Pyrazoles therapeutic use, Structure-Activity Relationship, Cyclin-Dependent Kinase 2 antagonists & inhibitors, Enzyme Inhibitors chemical synthesis, Piperidines chemical synthesis, Pyrazoles chemical synthesis
Abstract

The application of fragment-based screening techniques to cyclin dependent kinase 2 (CDK2) identified multiple (>30) efficient, synthetically tractable small molecule hits for further optimization. Structure-based design approaches led to the identification of multiple lead series, which retained the key interactions of the initial binding fragments and additionally explored other areas of the ATP binding site. The majority of this paper details the structure-guided optimization of indazole (6) using information gained from multiple ligand-CDK2 cocrystal structures. Identification of key binding features for this class of compounds resulted in a series of molecules with low nM affinity for CDK2. Optimisation of cellular activity and characterization of pharmacokinetic properties led to the identification of 33 (AT7519), which is currently being evaluated in clinical trials for the treatment of human cancers.

Published
2008
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3. Fragment-based discovery of mexiletine derivatives as orally bioavailable inhibitors of urokinase-type plasminogen activator.

Author

Frederickson M, Callaghan O, Chessari G, Congreve M, Cowan SR, Matthews JE, McMenamin R, Smith DM, Vinković M, and Wallis NG

Subjects
Administration, Oral, Animals, Biological Availability, Crystallography, X-Ray, Mexiletine chemistry, Mexiletine pharmacology, Models, Molecular, Rats, Stereoisomerism, Structure-Activity Relationship, Urokinase-Type Plasminogen Activator chemistry, Mexiletine analogs & derivatives, Mexiletine chemical synthesis, Urokinase-Type Plasminogen Activator antagonists & inhibitors
Abstract

Fragment-based lead discovery has been applied to urokinase-type plasminogen activator (uPA). The (R)-enantiomer of the orally active drug mexiletine 5 (a fragment hit from X-ray crystallographic screening) was the chemical starting point. Structure-aided design led to elaborated inhibitors that retained the key interactions of (R)-5 while gaining extra potency by simultaneously occupying neighboring regions of the active site. Subsequent optimization led to 15, a potent, selective, and orally bioavailable inhibitor of uPA.

Published
2008
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