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

Abstract Purpose: Recent developments of second generation Hsp90 inhibitors suggested a potential fordevelopment of this class of molecules also in tumors that have become resistant to molecular targetedagents. Disease progression is often due to brain metastases, sometimes related to insufficient drugconcentrations within the brain. Our objective was to identify and characterize a novel inhibitor of Hsp90able to cross the blood–brain barrier (BBB).ExperimentalDesign:HereisdescribedadetailedbiochemicalandcrystallographiccharacterizationofNMS-E973. Mechanism-based anticancer activity was described in cell models, including models ofresistance to kinase inhibitors. Pharmacokinetics properties were followed in plasma, tumor, liver, andbrain. In vivo activity and pharmacodynamics, as well as the pharmacokinetic/pharmacodynamic relation-ships, were evaluated in xenografts, including an intracranially implanted melanoma model.Results:NMS-E973,representativeofanovelisoxazole-derivedclassofHsp90inhibitors,bindsHsp90awithsubnanomolaraffinityandhighselectivitytowardskinases,aswellasotherATPases.Itpossessespotentantiproliferative activity against tumor cell lines and a favorable pharmacokinetic profile, with selectiveretention in tumor tissue and ability to cross the BBB. NMS-E973 induces tumor shrinkage in differenthuman 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 melanomamodel.Conclusions:Overall,theefficacyprofileofNMS-E973suggestsapotentialfordevelopmentindifferentclinical settings, including tumors that have become resistant to molecular targeted agents, particularly incases of tumors which reside beyond the BBB. Clin Cancer Res; 19(13); 3520–32. 2013 AACR.