We will present studies to evaluate different p97 inhibitors against two ATPase domains of p97 and a few p97-p97 complexes. Our studies identify several potential starting points for future SAR analyses, to improve the potencies of D1-specific inhibitors and selective inhibitors of the p97–p47 complex. It also highlights the potential importance of context-based inhibition of p97 ATPase activity. The important implications of this study are: 1) To improve SAR studies of p97 inhibitors in vitro, one needs to use D1 and D2 mutants to determine the extent to which compounds inhibit the D1 and D2 sites. 2) To correlate in vitro, cellular, and in vivo potencies of p97 inhibitors, one needs to consider the presence of different p97–cofactor complexes. 3) Further work is needed to develop specific cell-based assays for specific p97–cofactor complexes, to facilitate the development of complex-specific inhibitors.

Evaluating p97 inhibitor analogues for potency against different p97-p97 cofactor complexes

254th National Meeting (2017)

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