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Dissecting Programmed Cell Death with Small Molecules.
Accounts of Chemical Research ( IF 16.4 ) Pub Date : 2020-04-16 , DOI: 10.1021/acs.accounts.9b00600 Yingjie Bai 1 , Hiu C Lam 1 , Xiaoguang Lei 1, 2
Accounts of Chemical Research ( IF 16.4 ) Pub Date : 2020-04-16 , DOI: 10.1021/acs.accounts.9b00600 Yingjie Bai 1 , Hiu C Lam 1 , Xiaoguang Lei 1, 2
Affiliation
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ConspectusProgrammed cell death (PCD) is fundamentally an indispensable process in all cellular activities, including cell development, wound healing, and immune surveillance of tumors (Galluzzi, L. et al. Cell Death Differ. 2018, 25, 486-541). Malfunctioning of PCD has been shown to be closely related to human diseases such as acute pancreatitis, neurodegenerative diseases, and diverse types of cancers. To date, multiple PCD processes have been discovered and the corresponding regulatory pathways have been elucidated. For example, apoptosis and autophagy are two PCD mechanisms that have been well studied by sophisticated models and probe toolkits. However, limited genetic and chemical tools for other types of PCD hamper the elucidation of their molecular mechanisms. Our group has been studying PCD using both function-oriented synthesis and chemical biology strategies, including the development of diverse chemical probes based on novel PCD modulators. For instance, in the development of downstream programmed necrosis (or necroptosis) inhibitor necrosulfonamide, we used a chemical probe to unveil a functional protein that was not previously implicated in necroptosis, mixed lineage kinase domain-like protein (MLKL). In addition, high throughput screening and medicinal chemistry enabled the discovery of bioymifi, a small molecule agonist which selectively causes oligomerization of the death receptor 5 (DR5), to induce extrinsic apoptosis. Furthermore, we developed a biomimetic synthetic strategy based on diverse Diels-Alder reactions in the total syntheses of ainsliadimers A and B, ainsliatrimers A and B, and gonchnatiolides A-C, which are natural product inhibitors or activators for PCD. Using synthetic ainsliadimer A probe, we elucidated that ainsliadimer A inhibits the NF-κB pathway by covalently binding to Cys46 of IKKβ and triggers apoptosis of cancer cells. We have also revealed that IKKβ is allosterically inhibited by ainsliadimer A. In addition to total synthesis, we have developed a bioorthogonal click hetero-Diels-Alder cycloaddition of vinyl thioether and o-quinolinone quinone methide (TQ-ligation) to facilitate small molecule target identification. The combination of total synthesis and TQ-ligation enables subcellular imaging and identification of the cellular target of ainsliatrimer A to be PPARγ. In addition, TQ-ligation has been applied in the discovery of heat shock protein 90 (HSP90) as one of the functional target proteins for kongensin A. We also confirmed that kongensin A covalently attaches to Cys420 within HSP90 and demonstrated that kongensin A blocks the interaction between HSP90 and CDC37 and subsequently inhibits necroptosis. Our development of these diverse PCD modulators provides not only effective chemical tools for fundamental biomedical research, but also the foundation for drug discovery targeting important human diseases such as cancers and inflammation caused by malfunction of PCD.
中文翻译：
用小分子解剖程序性细胞死亡。
程序性细胞死亡（PCD）从根本上讲是所有细胞活动中必不可少的过程，包括细胞发育，伤口愈合以及对肿瘤的免疫监视（Galluzzi，L.等人Cell Death Differ.2018，25，486-541）。PCD的功能异常已被证明与人类疾病（例如急性胰腺炎，神经退行性疾病和各种癌症）密切相关。迄今为止，已经发现了多种PCD过程，并且已经阐明了相应的调节途径。例如，凋亡和自噬是两种PCD机制，已通过复杂的模型和探针工具包进行了深入研究。但是，用于其他类型PCD的有限的遗传和化学工具阻碍了其分子机制的阐明。我们的小组一直在使用面向功能的合成和化学生物学策略研究PCD，包括基于新型PCD调节剂的多种化学探针的开发。例如，在下游程序性坏死（或坏死性病变）抑制剂坏死磺酰胺的研发中，我们使用化学探针揭示了以前不参与坏死性病变的功能蛋白，即混合谱系激酶域样蛋白（MLKL）。此外，高通量筛选和药物化学使人们能够发现生物象征物，这是一种小分子激动剂，可选择性导致死亡受体5（DR5）的寡聚，从而诱导外源性细胞凋亡。此外，我们在拟南芥A和B，拟南芥A和B的总合成中，基于多种Diels-Alder反应，开发了仿生合成策略。和gonchnatiolides AC，它们是PCD的天然产物抑制剂或活化剂。我们使用合成的ainsliadimer A探针阐明了ainsliadimer A通过共价结合IKKβ的Cys46抑制NF-κB途径并触发了癌细胞的凋亡。我们还发现，IKSβ被ainsliadimer A变构抑制。除了全合成外，我们还开发了乙烯基硫醚和邻喹啉酮醌甲基化物（TQ-连接）的生物正交点击异Diels-Alder环加成反应（TQ-连接），以促进小分子靶标的形成。识别。全合成和TQ-连接的结合使得亚细胞三聚体A的细胞靶标为PPARγ的亚细胞成像和鉴定成为可能。此外，TQ连接已应用于发现热休克蛋白90（HSP90）作为孔菌素A的功能靶蛋白之一。我们还证实了孔菌素A共价附着于HSP90中的Cys420，并证明了孔菌素A阻断了HSP90之间的相互作用和CDC37，随后抑制坏死病。我们对这些多样的PCD调节剂的开发，不仅为基础生物医学研究提供了有效的化学工具，而且为针对重要人类疾病（例如由PCD失灵引起的癌症和炎症）的药物开发奠定了基础。
更新日期：2020-04-16
中文翻译：
用小分子解剖程序性细胞死亡。
程序性细胞死亡（PCD）从根本上讲是所有细胞活动中必不可少的过程，包括细胞发育，伤口愈合以及对肿瘤的免疫监视（Galluzzi，L.等人Cell Death Differ.2018，25，486-541）。PCD的功能异常已被证明与人类疾病（例如急性胰腺炎，神经退行性疾病和各种癌症）密切相关。迄今为止，已经发现了多种PCD过程，并且已经阐明了相应的调节途径。例如，凋亡和自噬是两种PCD机制，已通过复杂的模型和探针工具包进行了深入研究。但是，用于其他类型PCD的有限的遗传和化学工具阻碍了其分子机制的阐明。我们的小组一直在使用面向功能的合成和化学生物学策略研究PCD，包括基于新型PCD调节剂的多种化学探针的开发。例如，在下游程序性坏死（或坏死性病变）抑制剂坏死磺酰胺的研发中，我们使用化学探针揭示了以前不参与坏死性病变的功能蛋白，即混合谱系激酶域样蛋白（MLKL）。此外，高通量筛选和药物化学使人们能够发现生物象征物，这是一种小分子激动剂，可选择性导致死亡受体5（DR5）的寡聚，从而诱导外源性细胞凋亡。此外，我们在拟南芥A和B，拟南芥A和B的总合成中，基于多种Diels-Alder反应，开发了仿生合成策略。和gonchnatiolides AC，它们是PCD的天然产物抑制剂或活化剂。我们使用合成的ainsliadimer A探针阐明了ainsliadimer A通过共价结合IKKβ的Cys46抑制NF-κB途径并触发了癌细胞的凋亡。我们还发现，IKSβ被ainsliadimer A变构抑制。除了全合成外，我们还开发了乙烯基硫醚和邻喹啉酮醌甲基化物（TQ-连接）的生物正交点击异Diels-Alder环加成反应（TQ-连接），以促进小分子靶标的形成。识别。全合成和TQ-连接的结合使得亚细胞三聚体A的细胞靶标为PPARγ的亚细胞成像和鉴定成为可能。此外，TQ连接已应用于发现热休克蛋白90（HSP90）作为孔菌素A的功能靶蛋白之一。我们还证实了孔菌素A共价附着于HSP90中的Cys420，并证明了孔菌素A阻断了HSP90之间的相互作用和CDC37，随后抑制坏死病。我们对这些多样的PCD调节剂的开发，不仅为基础生物医学研究提供了有效的化学工具，而且为针对重要人类疾病（例如由PCD失灵引起的癌症和炎症）的药物开发奠定了基础。
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