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Design and Synthesis of 4-(Heterocyclic Substituted Amino)-1H-Pyrazole-3-Carboxamide Derivatives and Their Potent Activity against Acute Myeloid Leukemia (AML)

1
School of Pharmacy, Henan University of Chinese Medicine, Zhengzhou 450046, China
2
School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China
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Collaborative Innovation Center for Respiratory Disease Diagnosis, Treatment & Chinese Medicine Development of Henan Province, Henan University of Chinese Medicine, Zhengzhou 450046, China
4
School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(22), 5739; https://doi.org/10.3390/ijms20225739
Received: 28 October 2019 / Revised: 12 November 2019 / Accepted: 13 November 2019 / Published: 15 November 2019
(This article belongs to the Section Molecular Pharmacology)
Fms-like receptor tyrosine kinase 3 (FLT3) has been emerging as an attractive target for the treatment of acute myeloid leukemia (AML). By modifying the structure of FN-1501, a potent FLT3 inhibitor, 24 novel 1H-pyrazole-3-carboxamide derivatives were designed and synthesized. Compound 8t showed strong activity against FLT3 (IC50: 0.089 nM) and CDK2/4 (IC50: 0.719/0.770 nM), which is more efficient than FN-1501(FLT3, IC50: 2.33 nM; CDK2/4, IC50: 1.02/0.39 nM). Compound 8t also showed excellent inhibitory activity against a variety of FLT3 mutants (IC50 < 5 nM), and potent anti-proliferative effect within the nanomolar range on acute myeloid leukemia (MV4-11, IC50: 1.22 nM). In addition, compound 8t significantly inhibited the proliferation of most human cell lines of NCI60 (GI50 < 1 μM for most cell lines). Taken together, these results demonstrated the potential of 8t as a novel compound for further development into a kinase inhibitor applied in cancer therapeutics. View Full-Text
Keywords: 1H-pyrazole-3-carboxamide; AML; Cyclin-dependent kinases; fms-like receptor tyrosine kinase 3; protein kinase inhibitors; anti-cancer 1H-pyrazole-3-carboxamide; AML; Cyclin-dependent kinases; fms-like receptor tyrosine kinase 3; protein kinase inhibitors; anti-cancer
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MDPI and ACS Style

Zhi, Y.; Wang, Z.; Yao, C.; Li, B.; Heng, H.; Cai, J.; Xiang, L.; Wang, Y.; Lu, T.; Lu, S. Design and Synthesis of 4-(Heterocyclic Substituted Amino)-1H-Pyrazole-3-Carboxamide Derivatives and Their Potent Activity against Acute Myeloid Leukemia (AML). Int. J. Mol. Sci. 2019, 20, 5739. https://doi.org/10.3390/ijms20225739

AMA Style

Zhi Y, Wang Z, Yao C, Li B, Heng H, Cai J, Xiang L, Wang Y, Lu T, Lu S. Design and Synthesis of 4-(Heterocyclic Substituted Amino)-1H-Pyrazole-3-Carboxamide Derivatives and Their Potent Activity against Acute Myeloid Leukemia (AML). International Journal of Molecular Sciences. 2019; 20(22):5739. https://doi.org/10.3390/ijms20225739

Chicago/Turabian Style

Zhi, Yanle, Zhijie Wang, Chao Yao, Baoquan Li, Hao Heng, Jiongheng Cai, Li Xiang, Yue Wang, Tao Lu, and Shuai Lu. 2019. "Design and Synthesis of 4-(Heterocyclic Substituted Amino)-1H-Pyrazole-3-Carboxamide Derivatives and Their Potent Activity against Acute Myeloid Leukemia (AML)" International Journal of Molecular Sciences 20, no. 22: 5739. https://doi.org/10.3390/ijms20225739

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