NT5C2 INHIBITORS USEFUL FOR THE TREATMENT OF CHEMOTHERAPY RESISTANT ACUTE LYMPHOBLASTIC LEUKEMIA

摘要

Relapse and resistance to therapy is the most significant challenge in the treatment of lymphoblastic leukemia. Mutations in NT5C2 (a cytosolic nucleotidase activated by gain of function mutations in about 20% of relapse ALL cases) characteristically are associated with early relapse and progression under therapy and confer resistance to 6-mercaptopurine chemotherapy in vitro and in vivo. Activating mutations in NT5C2 disrupt intramolecular switch-off mechanisms responsible for returning the enzyme to its resting inactive state after activation and lock the NT5C2 protein in an active state similar to that induced by allosteric activators. Based on structure, NT5C2 inhibitors were developed for specific therapies for preventing and reversing 6-MP resistance in ALL.