title: NMS-E973, a novel synthetic inhibitor of Hsp90 with activity against multiple models of drug resistance to targeted agents, including intracranial metastases.
abstract: OBJECTIVE
  Recent developments of second generation Hsp90 inhibitors suggested a potential for development of this class of molecules also in tumors that have become resistant to molecular targeted agents. Disease progression is often due to brain metastases, sometimes related to insufficient drug concentrations within the brain. Our objective was to identify and characterize a novel inhibitor of Hsp90 able to cross the blood-brain barrier (BBB).
  
  
  METHODS
  Here is described a detailed biochemical and crystallographic characterization of NMS-E973. Mechanism-based anticancer activity was described in cell models, including models of resistance to kinase inhibitors. Pharmacokinetics properties were followed in plasma, tumor, liver, and brain. In vivo activity and pharmacodynamics, as well as the pharmacokinetic/pharmacodynamic relationships, were evaluated in xenografts, including an intracranially implanted melanoma model.
  
  
  RESULTS
  NMS-E973, representative of a novel isoxazole-derived class of Hsp90 inhibitors, binds Hsp90α with subnanomolar affinity and high selectivity towards kinases, as well as other ATPases. It possesses potent antiproliferative activity against tumor cell lines and a favorable pharmacokinetic profile, with selective retention in tumor tissue and ability to cross the BBB. NMS-E973 induces tumor shrinkage in different human tumor xenografts, and is highly active in models of resistance to kinase inhibitors. Moreover, consistent with its brain penetration, NMS-E973 is active also in an intracranially implanted melanoma model.
  
  
  CONCLUSIONS
  Overall, the efficacy profile of NMS-E973 suggests a potential for development in different clinical settings, including tumors that have become resistant to molecular targeted agents, particularly in cases of tumors which reside beyond the BBB.
authors.affiliation: Department of Biotechnology, Nerviano Medical Sciences Srl, Nerviano (MI), Italy. gianpaolo.fogliatto@nervianoms.com
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Fogliatto
authors.forename: Laura
authors.initials: L
authors.lastname: Gianellini
authors.forename: Maria G
authors.initials: MG
authors.lastname: Brasca
authors.forename: Elena
authors.initials: E
authors.lastname: Casale
authors.forename: Dario
authors.initials: D
authors.lastname: Ballinari
authors.forename: Marina
authors.initials: M
authors.lastname: Ciomei
authors.forename: Anna
authors.initials: A
authors.lastname: Degrassi
authors.forename: Anna
authors.initials: A
authors.lastname: De Ponti
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Germani
authors.forename: Marco
authors.initials: M
authors.lastname: Guanci
authors.forename: Mauro
authors.initials: M
authors.lastname: Paolucci
authors.forename: Paolo
authors.initials: P
authors.lastname: Polucci
authors.forename: Micaela
authors.initials: M
authors.lastname: Russo
authors.forename: Francesco
authors.initials: F
authors.lastname: Sola
authors.forename: Barbara
authors.initials: B
authors.lastname: Valsasina
authors.forename: Carlo
authors.initials: C
authors.lastname: Visco
authors.forename: Fabio
authors.initials: F
authors.lastname: Zuccotto
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
authors.forename: Eduard
authors.initials: E
authors.lastname: Felder
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.forename: Sergio
authors.initials: S
authors.lastname: Mantegani
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000556:secondary*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D009362:Neoplasm Metastasis; D009928:Organ Specificity / Q000187:drug effects; D011485:Protein Binding; D059748:Proteolysis / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; C585926:NMS-E973