<br>Linifanib 的支架跳跃设计 6-苯基异恶唑并[3,4-b]吡啶-3-胺衍生物作为 FLT3 抑制剂治疗急性髓系白血病,Letters in Drug Design & Discovery

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Linifanib 的支架跳跃设计 6-苯基异恶唑并[3,4-b]吡啶-3-胺衍生物作为 FLT3 抑制剂治疗急性髓系白血病
Letters in Drug Design & Discovery ( IF 1.2 ) Pub Date : 2023-06-22 , DOI: 10.2174/1570180820666230519140242
Shan-Liang Sun ₁ , Nian-Guang Li ₁ , Zhi-Hao Shi ₂ , Shi-Han Wu ₃ , Li-Jin Yang ₁ , Yi-Yuan Ma ₁ , Yu-Hao Cao ₁ , Zhen-Jiang Tong ₁ , Jia-Zhen Wu ₁ , Yi-Bo Wang ₁ , Jiu-Kai Sha ₁ , Ning Ding ₁ , Qiao-Li Liang ₁ , Liang Chang ₁ , Xiao-Long Wang ₁ , Jin-Ao Duan ₁ , Yan-Cheng Yu ₁ , Wei-Chen Dai _{1,

4} , Ke Xie ₂ , Xue-Jiao Leng ₁ , Xin Xue ₁

Affiliation

背景：急性髓系白血病（AML）是最常见的血癌类型。 Fmslike 酪氨酸激酶 3 (FLT3) 是 III 类受体酪氨酸激酶家族的成员。 70-100% 的急性髓系白血病患者中发现 FLT3 过度表达。 FLT3内部串联重复改变（ITD）和酪氨酸激酶结构域（TKD）是AML中最常见的分子改变，FLT3已成为AML有前途的药物靶点。目的：设计并合成一系列具有酰胺键的6-苯基异恶唑并[3,4-b]吡啶-3-胺衍生物F1-F15作为FLT3抑制剂，以寻找治疗AML的新先导化合物。方法：我们通过将 RECAP 工具与基于 Gilde 的 Core-Hopping 工具相结合，设计了原始的支架跳跃方案，以设计基于 Linifanib 的新型 FLT3 抑制剂。组装的抑制剂根据 Glide 生成的对接分数进行排名。选择前10名中未公开的化合物来设计一系列6-苯基异恶唑并[3,4-b]吡啶-3-胺衍生物作为FLT3抑制剂。测定了十五种化合物对FLT3和FLT3-ITD的激酶抑制活性。结构修饰化合物 F1-F15 的抗肿瘤活性针对 MOLM-13 和 MV4-11、携带 FLT3-ITD 突变体的典型 FLT3 依赖性人 AML 细胞和不依赖 FLT3 的人宫颈癌细胞系 HL-60（包含广泛的-类型 FLT3)。结果：构效关系（SAR）分析表明，F14 在 1 mM 浓度下可分别抑制 FLT3 和 FLT3-ITD 52% 和 45.55%。 F14 对 FLT3 依赖性人急性髓系白血病 (AML) 细胞系 MOLM-13 和 MV4-11（含有 FLT3-ITD 突变体）表现出有效的活性，IC50 值分别为 2.558 μM 和 1.785 μM。结论：F14可作为新型先导化合物进一步开发针对FLT3-ITD突变体的AML的FLT3抑制剂。

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

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.

更新日期：2023-06-22

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