Discovery of novel and highly potent small molecule inhibitors targeting FLT3-ITD for the treatment of acute myeloid leukemia using structure-based virtual screening and biological evaluation
Considering the essential role of FLT3-ITD mutations in the development of acute myeloid leukemia (AML), the research and development of FLT3 inhibitors hold significant therapeutic potential. In this study, we identified a novel, highly potent small molecule inhibitor, FLIN-4, targeting FLT3 throug...
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Frontiers Media S.A.
2025-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2025.1511257/full |
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| author | Kun Shi Kun Shi Ye Hong Ye Hong Ye Hong Huajing Liu Xiaotian Yang Fengzhen Wang Fengzhen Wang Yanming Zhang |
| author_facet | Kun Shi Kun Shi Ye Hong Ye Hong Ye Hong Huajing Liu Xiaotian Yang Fengzhen Wang Fengzhen Wang Yanming Zhang |
| author_sort | Kun Shi |
| collection | DOAJ |
| description | Considering the essential role of FLT3-ITD mutations in the development of acute myeloid leukemia (AML), the research and development of FLT3 inhibitors hold significant therapeutic potential. In this study, we identified a novel, highly potent small molecule inhibitor, FLIN-4, targeting FLT3 through structure-based virtual screening. Notably, FLIN-4 showed exceptional inhibitory effects in kinase activity inhibition assays, exhibiting a potent inhibitory effect against FLT3 (IC50 = 1.07 ± 0.04 nM). This potency was significantly superior to that of the known positive inhibitor Midostaurin, showing approximately 27 times higher inhibitory potency. Molecular dynamics simulations have confirmed the stable interaction between FLIN-4 and FLT3. Furthermore, cytotoxicity assays revealed that FLIN-4 has significant anti-proliferative activity against the AML cell line MV4-11 (IC50 = 1.31 ± 0.06 nM). Overall, these data suggest that FLIN-4, as a potential therapeutic candidate for AML, is valuable for further research and development. |
| format | Article |
| id | doaj-art-723ce1535922419fa60226561ef73563 |
| institution | Kabale University |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-723ce1535922419fa60226561ef735632025-02-03T06:33:34ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-02-011610.3389/fphar.2025.15112571511257Discovery of novel and highly potent small molecule inhibitors targeting FLT3-ITD for the treatment of acute myeloid leukemia using structure-based virtual screening and biological evaluationKun Shi0Kun Shi1Ye Hong2Ye Hong3Ye Hong4Huajing Liu5Xiaotian Yang6Fengzhen Wang7Fengzhen Wang8Yanming Zhang9Clinical Medical College, Xuzhou Medical University, Xuzhou, ChinaDepartment of Orthopedics, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical University, Xuzhou, ChinaClinical Medical College, Xuzhou Medical University, Xuzhou, ChinaDepartment of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, ChinaDepartment of Hematology, Binhai County People’s Hospital, Yancheng, Jiangsu, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, ChinaJiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, ChinaDepartment of Pharmacy, Suining People’s Hospital Affiliated to Xuzhou Medical University, Suining, ChinaDepartment of Hematology, The Affiliated Huai’an Hospital of Xuzhou Medical University, Huai’an, Jiangsu, ChinaConsidering the essential role of FLT3-ITD mutations in the development of acute myeloid leukemia (AML), the research and development of FLT3 inhibitors hold significant therapeutic potential. In this study, we identified a novel, highly potent small molecule inhibitor, FLIN-4, targeting FLT3 through structure-based virtual screening. Notably, FLIN-4 showed exceptional inhibitory effects in kinase activity inhibition assays, exhibiting a potent inhibitory effect against FLT3 (IC50 = 1.07 ± 0.04 nM). This potency was significantly superior to that of the known positive inhibitor Midostaurin, showing approximately 27 times higher inhibitory potency. Molecular dynamics simulations have confirmed the stable interaction between FLIN-4 and FLT3. Furthermore, cytotoxicity assays revealed that FLIN-4 has significant anti-proliferative activity against the AML cell line MV4-11 (IC50 = 1.31 ± 0.06 nM). Overall, these data suggest that FLIN-4, as a potential therapeutic candidate for AML, is valuable for further research and development.https://www.frontiersin.org/articles/10.3389/fphar.2025.1511257/fullFLT3-ITD mutationacute myeloid leukemia (AML)small molecule inhibitorstructure-based virtual screeningbiological evaluation |
| spellingShingle | Kun Shi Kun Shi Ye Hong Ye Hong Ye Hong Huajing Liu Xiaotian Yang Fengzhen Wang Fengzhen Wang Yanming Zhang Discovery of novel and highly potent small molecule inhibitors targeting FLT3-ITD for the treatment of acute myeloid leukemia using structure-based virtual screening and biological evaluation Frontiers in Pharmacology FLT3-ITD mutation acute myeloid leukemia (AML) small molecule inhibitor structure-based virtual screening biological evaluation |
| title | Discovery of novel and highly potent small molecule inhibitors targeting FLT3-ITD for the treatment of acute myeloid leukemia using structure-based virtual screening and biological evaluation |
| title_full | Discovery of novel and highly potent small molecule inhibitors targeting FLT3-ITD for the treatment of acute myeloid leukemia using structure-based virtual screening and biological evaluation |
| title_fullStr | Discovery of novel and highly potent small molecule inhibitors targeting FLT3-ITD for the treatment of acute myeloid leukemia using structure-based virtual screening and biological evaluation |
| title_full_unstemmed | Discovery of novel and highly potent small molecule inhibitors targeting FLT3-ITD for the treatment of acute myeloid leukemia using structure-based virtual screening and biological evaluation |
| title_short | Discovery of novel and highly potent small molecule inhibitors targeting FLT3-ITD for the treatment of acute myeloid leukemia using structure-based virtual screening and biological evaluation |
| title_sort | discovery of novel and highly potent small molecule inhibitors targeting flt3 itd for the treatment of acute myeloid leukemia using structure based virtual screening and biological evaluation |
| topic | FLT3-ITD mutation acute myeloid leukemia (AML) small molecule inhibitor structure-based virtual screening biological evaluation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1511257/full |
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