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Adenosine triphosphate (ATP)–competitive p97 inhibitor CB-5339, the successor of CB-5083, is being evaluated in Phase 1 clinical trials for anti-cancer therapy. Different modes-of-action p97 inhibitors such as allosteric inhibitors are useful to overcome drug-induced resistance, one of the major problems of targeted therapy. We previously demonstrated that allosteric p97 inhibitor NMS-873 can overcome CB-5083-induced resistance in HCT116. Here we employed chemical proteomics and drug-induced thermal proteome changes to identify drug targets, in combination with drug-resistant cell lines to dissect on- and off-target effects. We found that NMS-873 but not CB-5083 affected glycometabolism. By establishing NMS-873-resistant HCT116 cell lines and performing both cell-based and proteomic analysis, we confirmed that NMS-873 dysregulates glycometabolism in a p97-independent manner. We then used proteome integral solubility alteration with a temperature-based method (PISA T) to identify NDUFAF5 as one of the potential targets of NMS-873 in the mitochondrial complex I. We also demonstrated that glycolysis inhibitor 2-DG enhanced the anti-proliferative effect of NMS-873. The polypharmacology of NMS-873 can be advantageous for anti-cancer therapy for colon cancer.

NMS-873 Leads to Dysfunctional Glycometabolism in A p97-Independent Manner in HCT116 Colon Cancer Cells