Screening And Mechanism Of Anti-leukemia Small Molecules

Leukemia is a group of heterogeneous malignant hematologic diseases. With the deepening of the research on leukemia, the therapeutic effects have been improved gradually. For example, acute promyelocytic leukemia has been considered as one of the curable malignant diseases with the use of all-trans retinoic acid and arsenic trioxide. However, for most of leukemia patients, the existing treatments are far from satisfactory. Although ome new methods such as immunotherapy and cell therapy have been adopted in some leukemia patients, chemotherapy remains the first-line therapy. In addition, bone marrow transplantation has great potential, but the high cost and limited donor sources are major bottleneck and GVHD and relapse after transplantation are unpredictable. Therefore, exploring new therapeutic targets and development of new drugs is significant and meaningful. In recent years, many studies found that epigenetic regulation plays an important role in the leukemia initiation and development. A large number of abnormal epigenetic modifications has been discovered in leukemia.In our research, we mainly addressed anti-leukemia small molecules and their mechanisms. In the first part, we obtained a new small molecular inhibitor of histone lysine methylatransferase G9a——DC_G066. Compared with known G9 a inhibitor, Bix-01294, DC_G066 had similar inhibition capacity but lower cytotoxicity to normal cells. In the second part, we focused on the study of immunosuppressor FTY720. We discovered that FTY720 could induce apoptosis of M2 subtype of acute myeloid leukemia(AML-M2) cells. This compound blocked the cell cycle at G0/G1 phase and displayed an in vivo therapeutic effect even stronger than the classical anti-leukemia drug Ara-C.