Identification of an AXL kinase inhibitor in triple-negative breast cancer by structure-based virtual screening and bioactivity test
Identification of an AXL kinase inhibitor in triple-negative breast cancer by structure-based virtual screening and bioactivity test
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DOI：
10.1111/cbdd.13977
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发表时间：
2021-10-29
影响因子：
3
通讯作者：
Shen, Yingying
中科院分区：
文献类型：
--
作者：
Li, Pei;Niu, Yuzhen;Shen, Yingying
乳腺癌是发生在乳腺腺上皮的恶性肿瘤，超过15%的患者为三阴性乳腺癌（TNBC）。因此，寻找TNBC的新靶点和靶向治疗药物迫在眉睫。AXL的过表达与TNBC细胞的运动性和侵袭性相关，这是乳腺癌治疗的潜在靶点。通过基于结构的虚拟筛选和生物测定试验，首次鉴定了化合物Y 041 -5921（对AXL激酶的IC 50 = 6.069 μ m，对MDA-MB-231细胞系的IC 50 = 4.1 μ m）。化合物Y 041 -5921能显著抑制TNBC细胞的增殖和侵袭，对正常永生化乳腺上皮细胞的毒性远低于临床常用的化疗药物。对多种恶性肿瘤细胞的增殖也有较好的抑制作用（对U251细胞、科洛细胞、PC-9细胞、CAKI-1细胞和MG-63细胞的IC_（50）分别为10.0m、7.1m、10.3m、11.4m和5.8m）。通过分子动力学模拟和结合自由能计算研究了Y 041 -5921与AXL的相互作用机理，确定了主要由非极性溶剂化作用贡献能量的关键残基（如Ala 565、Lys 567、Met 598、Leu 620、Pro621、Met 623、Lys 624、Arg 676、Asn 677和Met 679）。本工作报道的靶向AXL的小分子抑制剂Y 041 -5921将为TNBC的开发奠定基础和提供理论依据。
Breast cancer is a malignant tumor that occurs in the glandular epithelium of the breast, and more than 15% of the patients are triple-negative breast cancer (TNBC). Therefore, finding new targets and targeted therapeutic drugs for TNBC is urgent. Overexpression of the AXL is associated with motility and invasiveness of the TNBC cells, which is a potential target for breast cancer therapy. A compound Y041-5921 (IC50 = 6.069 mu m for AXL kinase and IC50 = 4.1 mu m for MDA-MB-231 cell line) was identified through structure-based virtual screening and bioassay test for the first time. The compound Y041-5921 could significantly inhibit the proliferation and invasion of the TNBC cells and the toxicity of Y041-5921 to normal immortalized breast epithelial cells was far lower than that of commonly used clinical chemotherapy drugs. Besides, it also had well inhibitory effect on the proliferation of many other malignant tumor cell lines (the IC50 value are 10.0 m, 7.1 m, 10.3 m, 11.4 m and 5.8 m for U251 cell, COLO cell, PC-9 cell, CAKI-1 cell and MG63 cell, respectively). The interaction mechanism between Y041-5921 and AXL was studied by molecular dynamics (MD) simulations and binding free energy calculation, and the key residues whose energy contribution mainly comes from non-polar solvation interaction (such as Ala565, Lys567, Met598, Leu620, Pro621, Met623, Lys624, Arg676, Asn677 and Met679) were identified. The small molecule inhibitors Y041-5921 targeting AXL reported in this work will lay a foundation and provide a theoretical basis for the development of the TNBC.