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    Home > Medical News > Medical Science News > Researchers have developed a third-generation new FLT3 kinase inhibition for the selective mutation of FLT3-ITD for acute myeloid leukemia.

    Researchers have developed a third-generation new FLT3 kinase inhibition for the selective mutation of FLT3-ITD for acute myeloid leukemia.

    • Last Update: 2021-02-17
    • Source: Internet
    • Author: User
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    Recently, Liu Qingsong and Liu Jing, researchers of the Strong Magnetic Field Science Center of Hefei Institute of Material Sciences of the Chinese Academy of Sciences, developed a new FLT3-ITD mutation selective new FLT3 kinase inhibitor CHMFL-FLT3-335 for acute myeloid leukemia. The findings are currently published online in the international journal Pharmaceutical Chemistry, Journal of Medicinal Chemistry (2018 Dec 19, DOI: 10.1021/acs.jmedchem.8b01594).
    Acute myeloid leukemia (AML) is the most common acute leukemia in adults due to the rapid penetration of myelin cells into the hematogenesis system characterized by bone marrow, blood and other tissues through cloning, proliferation, abnormal differentiation, etc., and the incidence of acute leukemia in adults increases with age, and the survival rate of patients is low. Studies have shown that 30% of AML is caused by FLT3 kinase mutations and is closely related to poor prognostics. Therefore, FLT3-ITD is considered an important molecular target for the treatment of AML. Much progress has been made in the research and development of inhibitors for this kinase target, with Novarma's PKC412 approved by the FDA in 2016 as the first FLT3 kinase inhibitor to be listed, followed by Gilteritinib, developed by Atellas in December 2018, approved for use in AML patients with FLT3-ITD plus, in addition to several FLT3 inhibitors in clinical studies. However, most FLT3 kinase inhibitors currently lack the selectivity between similarly structured cKIT kinases, and double inhibition of both may cause bone marrow inhibition toxicity. In addition, there is currently no known FLT3 kinase inhibitor to obtain the selectivity between FLT3 wild type and FLT3-ITD mutants, and FLT3 wild type plays an important role in the proliferation and differentiation of normal primitive hematocytes, degenerative cell progenitor cells, etc. Therefore, the development of new FLT3-ITD inhibitors with higher selectability is very important for both physiological and pathological research and will have potential clinical value.
    In the early work, the scientific research team developed a new type of FLT3-ITD-positive kinase inhibitor CHMFL-FLT3-122 with independent intellectual property rights based on the structure of Erotini, which has been approved for clinical trials by the National Drug Administration and entered into human clinical trials. In order to overcome the drug resistance problems caused by the secondary mutation of the common target drug, the team, based on the maternal nuclear structure of erutinib, further through rational design methods, broke through the limitations of erutinib as a type I FLT3 kinase inhibitor, and developed a new type II kinase inhibitor CHMFL-FLT3-213 that can overcome a variety of drug-resistant mutations.
    In this work, the researchers developed a new FLT3-ITD mutation-selective type II kinase inhibitor CHMFL-FLT3-335, starting with the structure of the nonse specific FLT3 inhibitor AZD2932 and sorafinib (type II multi-target kinase inhibitor). The compound showed effective inhibitory activity (GI50:30-80 nM) for a variety of different ITD mutations, and more importantly, it achieved 8x and greater than 300x selectivity between FLT3-ITD mutants and FLT3 wild types and cKIT kinases, respectively, greatly improving its theoretical safety window. In addition, CHMFL-FLT3-335 exhibited good selectivity in 468 different kinases/mutations (S score (35) - 0.02). CHMFL-FLT3-335 can effectively inhibit the proliferation of FLT3-ITD-positive AML cancer cell lines by inhibiting phosphorylation of FLT3 kinases and downstream signaling paths, inducing apoptosis, and blocking cell cycles in G0/G1. It also showed effective anti-proliferation effect on primary cells in FLT3-ITD-positive patients without significantly affecting the wild type of FLT3 progeny cells. Compared with PKC412, the compound showed good selectivity to normal exocytes (PBMC). In in vivo experiments, CHMFL-FLT3-335 showed good medicinality and was able to strongly inhibit tumor growth in mouse heterogeneity transplant tumor models of MV4-11 cells.
    the research was supported by key projects of the Joint Fund of the National Natural Science Foundation of China, the strategic pilot science and technology project of "personalized medicine" of the Chinese Academy of Sciences, and the key research projects of cutting-edge science of the Chinese Academy of Sciences. (Bio Valley)
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