Structure-based discovery of potent and selective small-molecule inhibitors targeting signal transducer and activator of transcription 3 (STAT3)
Structure-based discovery of potent and selective small-molecule inhibitors targeting signal transducer and activator of transcription 3 (STAT3)
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DOI：
10.1016/j.ejmech.2021.113525
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发表时间：
2021-05-14
影响因子：
6.7
通讯作者：
Wang, Yuanxiang
中科院分区：
文献类型：
--
作者：
Huang, Qiuyao;Zhong, Yan;Wang, Yuanxiang
由于STAT 3在癌症的发生和发展中的重要作用，它已被证实是一个有吸引力的抗癌靶点。然而，发现具有药物样性质的有效和选择性STAT 3小分子抑制剂仍然具有挑战性。本研究以STX-119和SH-4 -54为原料，通过缩合法合成了2-苯基喹啉类和2-芳基咪唑并[1，2-a]吡啶类化合物。我们的研究发现了许多高效和选择性的STAT 3抑制剂，例如具有2-苯基咪唑[1，2-a]吡啶特权结构的化合物39，其选择性抑制STAT 3的磷酸化并抑制随后的信号传导途径。此外，39抑制人三阴性乳腺癌（TNBC）细胞系的细胞生长、迁移和侵袭。因此，它在小鼠细胞系来源和患者来源的异种移植肿瘤模型中均实现了显著的剂量依赖性肿瘤生长抑制。这些结果清楚地表明，39是一种高效和选择性的STAT 3抑制剂。(C)2021 Elsevier Masson SAS。All rights reserved.
STAT3 has been validated as an attractive anticancer target due to its important roles in cancer initiation and progression. However, discovery of potent and selective STAT3 small-molecule inhibitors with druglike properties is still challenging. In this study, two series of substituted 2-phenylquinolines and 2-arylimidazo[1,2-a]pyridines were designed through structure-based drug discovery approach by condensing the privileged structures of STX-119 and SH4-54. Our study has resulted in the discovery of a number of highly potent and selective STAT3 inhibitors, exemplified by compound 39 with the privileged structure of 2-phenylimidazo[1,2-a]pyridine, which selectively inhibits phosphorylation of STAT3 and suppresses subsequent signaling pathway. Moreover, 39 inhibits cell growth, migration and invasion of human triple negative breast cancer (TNBC) cells lines. Consistently, it achieves significant and dose-dependent tumor growth inhibition in both cell line-derived and patient-derived xenograft tumor models in mice. These results clearly indicate that 39 is a highly potent and selective STAT3 inhibitor. (C) 2021 Elsevier Masson SAS. All rights reserved.