title: Discovery of novel oxazepine and diazepine carboxamides as two new classes of heat shock protein 90 inhibitors.
abstract: Two novel series of oxazepine and diazepine based HSP90 inhibitors are reported. This effort relied on structure based design and isothermal calorimetry to identify small drug like macrocycles. Computational modelling was used to build into a solvent exposed pocket near the opening of the ATP binding site, which led to potent inhibitors of HSP90 (25-30).
authors: Vertex Pharmaceuticals Incorporated, Department of Chemistry, 11010 Torreyana Road, San Diego, CA 92121, United States. Electronic address: timothy_neubert@vrtx.com.
authors: Timothy
authors: T
authors: Neubert
authors: Vertex Pharmaceuticals Incorporated, Department of Chemistry, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Mehdi
authors: M
authors: Numa
authors: Vertex Pharmaceuticals Incorporated, Department of Chemistry, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Justin
authors: J
authors: Ernst
authors: Vertex Pharmaceuticals Incorporated, Department of Chemistry, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Jeremy
authors: J
authors: Clemens
authors: Vertex Pharmaceuticals Incorporated, Department of Chemistry, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Paul
authors: P
authors: Krenitsky
authors: Vertex Pharmaceuticals Incorporated, Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Michael
authors: M
authors: Liu
authors: Vertex Pharmaceuticals Incorporated, Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Beth
authors: B
authors: Fleck
authors: Vertex Pharmaceuticals Incorporated, Department of Biology, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Lisa
authors: L
authors: Woody
authors: Vertex Pharmaceuticals Incorporated, Department of Structural Biology, 50 Northern Avenue, Boston, MA 02210, United States.
authors: Harmon
authors: H
authors: Zuccola
authors: Vertex Pharmaceuticals Incorporated, Department of Chemistry, 11010 Torreyana Road, San Diego, CA 92121, United States.
authors: Dean
authors: D
authors: Stamos
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000577:Amides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001381:Azepines / Q000737:chemistry; D001549:Benzamides / Q000737:chemistry / Q000378:metabolism; D001569:Benzodiazepines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D002463:Cell Membrane Permeability / Q000187:drug effects; D018360:Crystallography, X-Ray; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D061985:Madin Darby Canine Kidney Cells; D062105:Molecular Docking Simulation; D010077:Oxazepines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D062367:ortho-Aminobenzoates / Q000737:chemistry / Q000378:metabolism
chemical_list: C548545:2-fluoro-6-(tetrahydrofuran-3-ylamino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-1-yl)benzamide; D000577:Amides; D001381:Azepines; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D010077:Oxazepines; D062367:ortho-Aminobenzoates; D001569:Benzodiazepines; D000255:Adenosine Triphosphate
keywords: Diazepine; HSP90 inhibitor; Macrocycle; Oaxazepine; Structure based design