American Association for Cancer Research
10780432ccr123512-sup-fig_s1.pdf (32.09 kB)

Supplementary Figure S1 from NMS-E973, a Novel Synthetic Inhibitor of Hsp90 with Activity against Multiple Models of Drug Resistance to Targeted Agents, Including Intracranial Metastases

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journal contribution
posted on 2023-03-31, 17:49 authored by 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

Supplementary Figure S1 - PDF file 32K, Chemical structure of NMS-E973



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. Clin Cancer Res; 19(13); 3520–32. ©2013 AACR.