biostudies-literatureLi SNational Institute of Neurological Disorders and StrokeNINDS NIH HHS764https://www.ebi.ac.uk/biostudies/studies/S-EPMC9024726biostudies-literatureUnknown14(4)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 analysPharmaceuticsNMS-873 Leads to Dysfunctional Glycometabolism in A p97-Independent Manner in HCT116 Colon Cancer Cells.PMC9024726R01NS102279R01NS100815Zhang GLi SWang FChou TFfalseNMS-873 Leads to Dysfunctional Glycometabolism in A p97-Independent Manner in HCT116 Colon Cancer Cells.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 analys2022-01-01T00:00:00Z2022 Mar2026-05-18T03:14:19.213Z2025-04-04T10:02:19.552ZS-EPMC90247263545659810.3390/pharmaceutics14040764