CRCD2 is a small molecule NT5C2 nucleotidase inhibitor with enhanced 6-mercaptopurine cytotoxic activity. CRCD2 can effectively reverse 6-mercaptopurine resistance caused by mutations in the NT5C2 gene or non-genetic activation mechanisms. CRCD2 combined with 6-mercaptopurine can enhance its cytotoxic activity in NT5C2 wild-type leukemia, showing its potential in the treatment of acute lymphoblastic leukemia.