NMS-E973, a novel synthetic inhibitor of Hsp90 with activity against multiple models of drug resistance to targeted agents, including intracranial metastases.

Abstract

PURPOSE:

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).

EXPERIMENTAL DESIGN:

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: Gianpaolo Fogliatto, Laura Gianellini, Maria G Brasca, Elena Casale, Dario Ballinari, Marina Ciomei, Anna Degrassi, Anna De Ponti, Massimiliano Germani, Marco Guanci, Mauro Paolucci, Paolo Polucci, Micaela Russo, Francesco Sola, Barbara Valsasina, Carlo Visco, Fabio Zuccotto, Daniele Donati, Eduard Felder, Enrico Pesenti, Arturo Galvani, Sergio Mantegani, Antonella Isacchi
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 13 Pg. 3520-32 (Jul 01 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23674492 (Publication Type: Journal Article)
• Copyright: ©2013 AACR.

Chemical References

• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Isoxazoles
• NMS-E973

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Binding Sites
• Brain Neoplasms (drug therapy, metabolism, pathology, secondary)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• HSP90 Heat-Shock Proteins (antagonists & inhibitors, chemistry)
• Humans
• Inhibitory Concentration 50
• Isoxazoles (chemistry, pharmacokinetics, pharmacology)
• Mice
• Molecular Conformation
• Molecular Docking Simulation
• Neoplasm Metastasis
• Organ Specificity (drug effects)
• Protein Binding
• Proteolysis (drug effects)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays