Ursodeoxycholic Acid Platinum(IV) Conjugates as Antiproliferative and Antimetastatic Agents: Remodel the Tumor Microenvironment through Suppressing JAK2/STAT3 Signaling,Journal of Medicinal Chemistry

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Ursodeoxycholic Acid Platinum(IV) Conjugates as Antiproliferative and Antimetastatic Agents: Remodel the Tumor Microenvironment through Suppressing JAK2/STAT3 Signaling
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-18 , DOI: 10.1021/acs.jmedchem.4c01549
Yan Chen ₁ , Ming Zhang ₁ , Zhifang Liu ₁ , Ning Zhang ₁ , Qingpeng Wang ₁

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Tumor microenvironment (TME) is a pivotal factor driving the tumor metastasis and leading to the failure of tumor therapy. Here, a series of ursodeoxycholic acid platinum(IV) conjugates with potency in remodeling the TME through suppressing JAK2/STAT3 signaling was developed. A candidate was screened out, which displayed potent antiproliferative and antimetastatic performance both in vitro and in vivo. It displayed superior pharmacokinetic properties compared to cisplatin. Serious DNA injury was induced, and then mitochondria-mediated apoptosis was initiated through the Bcl-2/Bax/Caspase3 pathway. The JAK2/STAT3 and TGF-β1 signaling pathways were remarkably inhibited, and pro-death autophagy was subsequently promoted. The inflammatory and hypoxic TME was suppressed by downregulating COX-2, MMP9, and HIF-1α, which resulted in inhibited angiogenesis in tumors by inhibiting the HIF-1α/VEGFA axis. Additionally, the immunosuppressive TME was reversed by blocking the immune checkpoint PD-L1, further improving the density of CD3⁺ and CD8⁺ tumor-infiltrating lymphocytes, and promoting macrophage polarization from M2- to M1-type.

中文翻译：

熊去氧胆酸铂（IV）偶联物作为抗增殖和抗转移剂：通过抑制 JAK2/STAT3 信号传导重塑肿瘤微环境

肿瘤微环境（TME）是驱动肿瘤转移并导致肿瘤治疗失败的关键因素。在这里，开发了一系列熊去氧胆酸铂（IV）偶联物，通过抑制 JAK2/STAT3 信号传导重塑 TME。筛选出一名候选药物，该候选药物在体外和体内均表现出有效的抗增殖和抗转移性能。与顺铂相比，它显示出优越的药代动力学特性。诱导严重的 DNA 损伤，然后通过 Bcl-2/Bax/Caspase3 通路启动线粒体介导的细胞凋亡。JAK2/STAT3 和 TGF-β1 信号通路受到显著抑制，随后促进了促死亡自噬。通过下调 COX-2 、 MMP9 和 HIF-1α 来抑制炎症和缺氧 TME，从而通过抑制 HIF-1α/VEGFA 轴抑制肿瘤中的血管生成。此外，通过阻断免疫检查点 PD-L1 逆转免疫抑制 TME，进一步提高 CD3 ⁺ 和 CD8 ⁺ 肿瘤浸润淋巴细胞的密度，促进巨噬细胞从 M2 型极化为 M1 型。

更新日期：2024-09-18

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