Combining structure- and property-based optimization to identify selective FLT3-ITD inhibitors with good antitumor efficacy in AML cell inoculated mouse xenograft model

Heng, Hao; Wang, Zhijie; Li, Hongmei; Huang, Yatian; Lan, Qingyuan; Guo, Xiaoxing; Zhang, Liang; Zhi, Yanle; Cai, Jiongheng; Qin, Tianren; Li, Xiang; Wang, Shuxian; Chen, Yadong; Lü, Tao; Lü, Shan

doi:10.1016/j.ejmech.2019.05.021

Cited by 12 publications

(9 citation statements)

References 30 publications

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“…The construction method of FLT3 homology models was previously described by us and used in this work directly. The molecular docking and MD simulations were carried out using the Glide module and the Desmond module of Schrödinger as described in our previous publications. , …”

Section: Methodsmentioning

confidence: 99%

“…The molecular docking and MD simulations were carried out using the Glide module and the Desmond module of Schrodinger as described in our previous publications. 46,47 WB Assay. MV4-11 cells (3,000,000 per well) were plated in flatbottom six-well plates and then treated with different concentrations of compounds and DMSO.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…Previously, we discovered a highly potent and selective type I FLT3 inhibitor Lu-46 through continuous structural optimizations, which showed excellent in vitro growth inhibitory activity against MV4-11 cells and in vivo antitumor efficacy in MV4-11 xenograft mouse models. However, potencies of Lu-46 were weakened by the secondary FLT3-TKD mutations such as FLT3-ITD-D835V and FLT3-ITD-F691L in the transformed BaF3 cells . Herein, to promote addressing the obstacle of resistance, we started from Lu-46 to find out new and potent FLT3 inhibitors with the potential to overcome such drug resistance.…”

Section: Introductionmentioning

confidence: 99%

“…9,42−44 Therefore, development of new-generation FLT3 inhibitors targeting resistance-related secondary mutations represents a new direction for a more potent anti-AML drug, 9,42,45 which will contribute to overcoming drug resistance and thus improving the corresponding clinical treatment effects. Previously, we discovered a highly potent and selective type I FLT3 inhibitor Lu-46 through continuous structural optimizations, 46 which showed excellent in vitro growth inhibitory activity against MV4-11 cells and in vivo antitumor efficacy in MV4-11 xenograft mouse models. However, potencies of Lu-46 were weakened by the secondary FLT3-TKD mutations such as FLT3-ITD-D835V and FLT3-ITD-F691L in the transformed BaF3 cells.…”

Section: ■ Introductionmentioning

confidence: 99%

“…However, potencies of Lu-46 were weakened by the secondary FLT3-TKD mutations such as FLT3-ITD-D835V and FLT3-ITD-F691L in the transformed BaF3 cells. 46 Herein, to promote addressing the obstacle of resistance, we started from Lu-46 to find out new and potent FLT3 inhibitors with the potential to overcome such drug resistance. Through analyzing the binding mode of Lu-46 with FLT3, we rationally developed a series of 3-amine-pyrazole-5-benzimidazole compounds with high inhibitory activities against FLT3-ITD and several FLT3-ITD-TKD mutants.…”

Section: ■ Introductionmentioning

confidence: 99%

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Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations

et al. 2021

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%