title: Tricyclic series of heat shock protein 90 (Hsp90) inhibitors part I: discovery of tricyclic imidazo[4,5-c]pyridines as potent inhibitors of the Hsp90 molecular chaperone.
abstract: A novel class of heat shock protein 90 (Hsp90) inhibitors was developed after a low throughput screen (LTS) of a focused library containing approximately 21K compounds selected by virtual screening. The initial [1-{3-H-imidazo[4-5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one] (1) compound showed moderate activity (IC(50) = 7.6 μM on Hsp82, the yeast homologue of Hsp90). A high-resolution X-ray structure shows that compound 1 binds into an "induced" hydrophobic pocket, 10-15 Å away from the ATP/resorcinol binding site. Iterative cycles of structure-based drug design (SBDD) and chemical synthesis led to the design and preparation of analogues with improved affinity. These optimized molecules make productive interactions within the ATP binding site as reported by other Hsp90 inhibitors. This resulted in compound 8, which is a highly potent inhibitor in biochemical and cellular assays (K(d) = 0.35 nM on Hsp90; IC(50) = 30 nM on SKBr3 mammary carcinoma cells) and in an in vivo leukemia model.
authors.affiliation: Sanofi-Aventis Research and Development, 13 Quai Jules Guesde, BP 14, 94400 Vitry-sur-Seine, France.
authors.forename: François
authors.initials: F
authors.lastname: Vallée
authors.forename: Chantal
authors.initials: C
authors.lastname: Carrez
authors.forename: Fabienne
authors.initials: F
authors.lastname: Pilorge
authors.forename: Alain
authors.initials: A
authors.lastname: Dupuy
authors.forename: Annick
authors.initials: A
authors.lastname: Parent
authors.forename: Luc
authors.initials: L
authors.lastname: Bertin
authors.forename: Fabienne
authors.initials: F
authors.lastname: Thompson
authors.forename: Paul
authors.initials: P
authors.lastname: Ferrari
authors.forename: Florence
authors.initials: F
authors.lastname: Fassy
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lamberton
authors.forename: Anne
authors.initials: A
authors.lastname: Thomas
authors.forename: Rosalia
authors.initials: R
authors.lastname: Arrebola
authors.forename: Stéphane
authors.initials: S
authors.lastname: Guerif
authors.forename: Alexandre
authors.initials: A
authors.lastname: Rohaut
authors.forename: Victor
authors.initials: V
authors.lastname: Certal
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Ruxer
authors.forename: Thierry
authors.initials: T
authors.lastname: Gouyon
authors.forename: Cécile
authors.initials: C
authors.lastname: Delorme
authors.forename: Alain
authors.initials: A
authors.lastname: Jouanen
authors.forename: Jacques
authors.initials: J
authors.lastname: Dumas
authors.forename: Claudine
authors.initials: C
authors.lastname: Grépin
authors.forename: Cécile
authors.initials: C
authors.lastname: Combeau
authors.forename: Hélène
authors.initials: H
authors.lastname: Goulaouic
authors.forename: Norbert
authors.initials: N
authors.lastname: Dereu
authors.forename: Vincent
authors.initials: V
authors.lastname: Mikol
authors.forename: Patrick
authors.initials: P
authors.lastname: Mailliet
authors.forename: Hervé
authors.initials: H
authors.lastname: Minoux
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005449:Fluorenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007938:Leukemia / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005449:Fluorenes; D018841:HSP90 Heat-Shock Proteins; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; C568955:N-(4-(3H-imidazo(4,5-c)pyridin-2-yl)-9H-fluoren-9-yl)-1H-pyrrolo(2,3-b)pyridine-4-carboxamide; D011725:Pyridines; D000255:Adenosine Triphosphate