Compound 38(Leidos Biomedical Research)

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.