Methods and compositions for inhibition of the transitional endoplasmic reticulum ATPase

摘要

Compounds of Formulas I-XLIII are identified as direct inhibitors of p97 ATPase or of the degradation of a p97-dependent ubiquitin-proteasome system (UPS) substrate. Methods and compositions are disclosed for inhibiting p97 ATPase and the degradation of a p97-dependent UPS substrate, and for identifying inhibitors thereof.

主权项

1. A composition suitable for decreasing p97 ATPase activity and/or degradation of a p97 dependent ubiquitin-proteasome substrate, comprising: a compound of Formula VII, IX, XII, XX, XXI or XLIII, or a pegylated analog of the compound, a pharmaceutically acceptable salt of the compound or the analog, or any regioisomer or stereoisomer of the compound: Wherein, for Formula VII, R1, n, X, and Y are selected from the group consisting of combinations listed in Table 7:TABLE 7Cpd # R1nXYVII-3 H1OH, HVII-4 H1NHH, HVII-58-OMe1NHH, HVII-68-OMe1OH, HVII-7 8-OH1OH, HVII-88-Ph1OH, HVII-9 8-OCH2CH2OH1OH, HVII-108OCH2CH2NEt2 1OH, HVII-118-p-OMePh1OH, HVII-128-OMe1NMeH, HVII-138-OMe1NCOMeH, HVII-148-OCH2CH2OMe 1OH, HVII-168-OMe0NHNHVII-178-OMe0OY,Y together formone O as oxygen ofcarbonyl incorporatingboth Y'sVII-158-n-Butyl1OH, H Wherein, for Formula XII, R4 is selected from the group consisting of the moieties listed in Table 10:TABLE 10.1Cpd #R4Cpd #R4XII-4XII-8XII-7XII-10XII-2XII-11XII-9 Wherein for Formula XXI, R1 is 5,6-dimethyl;