Fragment-based hit discovery and structure-based optimization of aminotriazoloquinazolines as novel Hsp90 inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 22; no. 15; pp. 4135 - 4150
• Main Authors: Casale, Elena, Amboldi, Nadia, Brasca, Maria Gabriella, Caronni, Dannica, Colombo, Nicoletta, Dalvit, Claudio, Felder, Eduard R., Fogliatto, Gianpaolo, Galvani, Arturo, Isacchi, Antonella, Polucci, Paolo, Riceputi, Laura, Sola, Francesco, Visco, Carlo, Zuccotto, Fabio, Casuscelli, Francesco
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2014; Elsevier
• Subjects: Anti-cancer agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding Sites; Biochemistry & Molecular Biology; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Design; Drug Evaluation, Preclinical; FAXS-NMR screening; Fragment based hit discovery; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Hsp90 inhibitors; Humans; Hydrogen Bonding; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Molecular Dynamics Simulation; Pharmacology & Pharmacy; Physical Sciences; Protein Structure, Tertiary; Quinazolines - chemical synthesis; Quinazolines - chemistry; Quinazolines - pharmacology; Science & Technology; Structure-Activity Relationship; Structure-based design; FAXS-NMR screening; Anti-cancer agents; Hsp90 inhibitors; Fragment based hit discovery; Structure-based design; CHAPERONE HSP90; DESIGN; SERIES; IDENTIFICATION; LIBRARIES; NMS-E973; NMR; AGENTS; DERIVATIVES; BINDING
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.05.056

[Display omitted] In the last decade the heat shock protein 90 (Hsp90) has emerged as a major therapeutic target and many efforts have been dedicated to the discovery of Hsp90 inhibitors as new potent anticancer agents. Here we report the identification of a novel class of Hsp90 inhibitors by means of a biophysical FAXS-NMR based screening of a library of fragments. The use of X-ray structure information combined with modeling studies enabled the fragment evolution of the initial triazoloquinazoline hit to a class of compounds with nanomolar potency and drug-like properties suited for further lead optimization.