Antitumor Efficacy of 1,2,4-Triazole-Based VCP/p97 Allosteric Inhibitors

The AAA ATPase p97 (VCP) plays a crucial role in maintaining
protein
homeostasis through the ubiquitin-proteosome pathway, as well as other
mechanisms. Due to the increased mutational load and protein quality
control failures in cancer cells, p97 is a potential target for cancer
therapy. Here, we highlight the optimization of the previously reported
3-thioalkyl-1,2,4-triazol-pyridyl allosteric inhibitor scaffold and
identify two compounds (25 and 38) with
low-nanomolar biochemical potency, submicromolar cellular inhibition,
in vivo effects on biomarkers of VCP inhibition, and antitumor efficacy
in mouse xenograft tumor models. Furthermore, compound 38 demonstrated robust inhibition of VCP ATP-site mutant proteins and
growth of cells resistant to the known ATP-competitive inhibitor CB-5083.