التفاصيل البيبلوغرافية
| العنوان: |
Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations |
| المؤلفون: |
Zhijie Wang (283745), Jiongheng Cai (11467041), Jiwei Ren (9256994), Yun Chen (279569), Yingli Wu (1772014), Jie Cheng (294193), Kun Jia (747683), Fei Huang (9205), Zitian Cheng (11467044), Tiancheng Sheng (11467047), Shiyu Song (733585), Hao Heng (9161263), Yifan Zhu (417526), Weifang Tang (1478896), Hongmei Li (51944), Tao Lu (39406), Yadong Chen (621664), Shuai Lu (158723) |
| سنة النشر: |
2021 |
| المجموعة: |
Smithsonian Institution: Digital Repository |
| مصطلحات موضوعية: |
Biophysics, Biochemistry, Cell Biology, Genetics, Molecular Biology, Pharmacology, Biotechnology, Immunology, Cancer, Hematology, Infectious Diseases, Chemical Sciences not elsewhere classified, strongly inhibited phosphorylation, significant clinical challenge, selective inhibitory activities, possessed equivalent potency, downstream signaling factors, 11 xenograft models, flt3 inhibitor resistance, transformed baf3 cells, 67 , potent flt3 inhibitor, exhibited potent, 11 cells, flt3 could, taken together, secondary mutations, ribose region, results demonstrated, main mechanism |
| الوصف: |
Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitor resistance that presents a significant clinical challenge. Herein, a series of pyrazole-3-amine derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. The structure–activity relationship and molecular dynamics simulation studies illustrated that the ribose region of FLT3 could be occupied to help address the obstacle of secondary mutations. Among those derivatives, compound 67 exhibited potent and selective inhibitory activities against FLT3-ITD-positive acute myeloid leukemia (AML) cells and possessed equivalent potency against transformed BaF3 cells with a variety of secondary mutations. Besides, cellular mechanism assays demonstrated that 67 strongly inhibited phosphorylation of FLT3 and its downstream signaling factors, as well as induced cell cycle arrest and apoptosis in MV4-11 cells. In the MV4-11 xenograft models, 67 exhibited potent antitumor potency without obvious toxicity. Taken together, these results demonstrated that 67 might be a drug candidate for the treatment of FLT3-ITD-positive AML. |
| نوع الوثيقة: |
dataset |
| اللغة: |
unknown |
| Relation: |
https://figshare.com/articles/dataset/Discovery_of_a_Potent_FLT3_Inhibitor_LT-850-166_with_the_Capacity_of_Overcoming_a_Variety_of_FLT3_Mutations/16661511 |
| DOI: |
10.1021/acs.jmedchem.1c01196.s004 |
| الاتاحة: |
https://doi.org/10.1021/acs.jmedchem.1c01196.s004 |
| Rights: |
CC BY-NC 4.0 |
| رقم الانضمام: |
edsbas.46B20598 |
| قاعدة البيانات: |
BASE |