Scaffold-hopping of Linifanib to Design 6-phenylisoxazolo[3,4-b]pyridin-3-amine Derivatives as FLT3 Inhibitors for Treating Acute Myeloid Leukemia

Title:Scaffold-hopping of Linifanib to Design 6-phenylisoxazolo[3,4-b]pyridin-3-amine Derivatives as FLT3 Inhibitors for Treating Acute Myeloid Leukemia

Volume: 21 Issue: 10

Author(s): Shi-Han Wu, Yi-Yuan Ma, Li-Jin Yang, Yu-Hao Cao, Zhen-Jiang Tong, Jia-Zhen Wu, Yi-Bo Wang, Jiu-Kai Sha, Ning Ding, Qiao-Li Liang, Liang Chang, Xiao-Long Wang, Jin-Ao Duan, Yan-Cheng Yu, Wei-Chen Dai, Ke Xie, Xue-Jiao Leng, Xin Xue*, Shan-Liang Sun*, Nian-Guang Li*Zhi-Hao Shi*

Affiliation:

• National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu, 210023, China

• National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu, 210023, China

• National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu, 210023, China

• Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639, Longmian Avenue, Nanjing, Jiangsu, 211198, China

Keywords: Acute myeloid leukemia, FLT3, FLT3-ITD, MOLM-13, MV4-11, structure–activity relationship (SAR).

Abstract:

Background: Acute myeloid leukemia (AML) is the most common type of blood cancer. Fmslike tyrosine kinase 3 (FLT3) is a member of the class III receptor tyrosine kinase family. Overexpression of FLT3 was found in 70-100% of patients with acute myeloid leukaemia. FLT3 internal tandem duplication alteration (ITD) and the tyrosine kinase domain (TKD) are the most common molecular alteration in AML, and FLT3 has become a promising drug target for AML.

Objective: A series of 6-phenylisoxazolo[3,4-b]pyridin-3-amine derivatives F1–F15 with amide bonds as FLT3 inhibitors were designed and synthesized in order to find a new lead compound to treat AML.

Methods: We designed an original scaffold-hopping protocol by combing the RECAP tool with the Gilde-Based Core-Hopping tool to design novel FLT3 inhibitors based on Linifanib. Inhibitors assembled were ranked by the docking scores generated by Glide. Compounds undisclosed among the top 10 were selected to design a series of 6-phenylisoxazolo[3,4-b]pyridin-3-amine derivatives as FLT3 inhibitors. The kinase inhibitory activities of the fifteen compounds were assayed on FLT3 and FLT3-ITD. The antitumor activities of the structurally modified compounds F1–F15 were evaluated against MOLM-13 and MV4-11, typical FLT3-dependent human AML cells carrying FLT3-ITD mutants and the FLT3- independent human cervical carcinoma cell line HL-60 (harboring wide-type FLT3).

Results: Structure–activity relationship (SAR) analysis showed that F14 could inhibit FLT3 and FLT3- ITD by 52% and 45.55%, respectively, at the concentration of 1 mΜ. F14 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines, MOLM-13, and MV4-11 (harboring FLT3-ITD mutant) with IC50 values of 2.558 μM and 1.785 μM, respectively.

Conclusion: F14 could be used as a novel lead compound to further develop FLT3 inhibitors against AML with FLT3-ITD mutant.

Cite this article as:

Wu Shi-Han, Ma Yi-Yuan, Yang Li-Jin, Cao Yu-Hao, Tong Zhen-Jiang, Wu Jia-Zhen, Wang Yi-Bo, Sha Jiu-Kai, Ding Ning, Liang Qiao-Li, Chang Liang, Wang Xiao-Long, Duan Jin-Ao, Yu Yan-Cheng, Dai Wei-Chen, Xie Ke, Leng Xue-Jiao, Xue Xin*, Sun Shan-Liang*, Li Nian-Guang*, Shi Zhi-Hao*, Scaffold-hopping of Linifanib to Design 6-phenylisoxazolo[3,4-b]pyridin-3-amine Derivatives as FLT3 Inhibitors for Treating Acute Myeloid Leukemia, Letters in Drug Design & Discovery 2024; 21 (10) . https://dx.doi.org/10.2174/1570180820666230519140242