Leukemia is a type of malignant clonal disease of hematopoietic stem cells. Clonal leukemia cells proliferate and accumulate in bone marrow and other hematopoietic tissues due to uncontrolled proliferation, differentiation disorders, and blocked apoptosis, and infiltrate other non-hematopoietic tissues and organs, while inhibiting normal hematopoietic function.
Recently, Liu Jing's research group and Liu Qingsong research group of the Institute of Strong Magnetic Fields, Hefei Institute of Material Science, Chinese Academy of Sciences, collaborated to discover a new high-activity, selective PI3Kd kinase small molecule inhibitor CHMFL-PI3KD-317.
PI3Kd is closely related to B cell tumors such as chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), follicular lymphoma (FL) and small lymphocytic lymphoma (SLL). PI3Kd kinase is a treatment for B cell-associated tumors. A drug target. The study identified a highly active, selective novel PI3Kd kinase inhibitor, CHMFL-PI3KD-317, by analyzing the structure of PI3Kd kinase using a structure-based drug design concept. The results showed that CHMFL-PI3KD-317 can effectively inhibit the activity of PI3Kd kinase (IC50 = 6 nM), while achieving selectivity (10-300 fold) between PI3Kd and other subtypes of the PI3K family, and the inhibitor PI3Kd-mediated phosphorylation of Akt T308 was significantly inhibited (EC50 = 4.3 nM). Further tests on the binding strength of 468 kinases showed that CHMFL-PI3KD-317 also has a very high selectivity in the kinase group. Furthermore, this inhibitor showed significant tumor suppressive effects in a mouse xenograft model of acute myeloid leukemia cell MOLM14.
The relevant research results were published in the journal Journal of Medicinal Chemistry in the field of medicinal chemistry and have been applied for patent protection. The research was funded by the “Millions of People†Youth Talents Program, the National Natural Science Foundation, the Chinese Academy of Sciences' Strategic Pilot Science and Technology Project, the Anhui Provincial Natural Science Foundation, and the Chinese Academy of Sciences' Frontier Science Key Research Program. Associate researcher Liang Xiaofei, postdoctoral Wang Ao Li, graduate students Li Feng, Chen Cheng, Jiang Zongru and others as the main contributors completed the work.
Source: Hefei Research Institute
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