Innovation Center of Nursing Research and Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu 610041, China.
Laboratory of Natural and Targeted Small Molecule Drugs, State Key Laboratory of Biotherapy and Cancer Center and Collaborative Innovation Center of Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China.
J Med Chem. 2024 Jan 11;67(1):165-179. doi: 10.1021/acs.jmedchem.3c01039. Epub 2023 Dec 20.
Cytoplasmic vacuolation-associated cell death, known as methuosis, offers a promising nonapoptotic approach for cancer treatment. In this study, we outline the synthesis and evaluation of potent methuosis-inducing compounds. These compounds selectively induce cell death, characterized by extensive cytoplasmic vacuolation in HeLa and MDA-MB-231 cells. Notably, compound exhibited a remarkable interaction with PIKfyve kinase, boasting a value of 0.47 nM, surpassing the positive controls D-13 and MOMIPP in potency. Furthermore, it is important to highlight that cell death induced by compound is unequivocally attributed to methuosis as it differs from apoptosis, necrosis, or autophagy. Importantly, when administered orally, effectively inhibited tumor growth in a HeLa xenograft model without any apparent signs of toxicity. These results underscore the potential of as a valuable tool for in-depth investigations into the mechanisms of methuosis and as a promising lead compound to guide structural optimization.
细胞质空泡化相关的细胞死亡，即溶酶体过度胀亡，为癌症治疗提供了一种很有前途的非细胞凋亡方法。在本研究中，我们概述了强效诱导溶酶体过度胀亡化合物的合成和评估。这些化合物能选择性诱导细胞死亡，在 HeLa 和 MDA-MB-231 细胞中表现为广泛的细胞质空泡化。值得注意的是，化合物 对 PIKfyve 激酶具有显著的相互作用，其 值为 0.47 nM，在效力上超过阳性对照 D-13 和 MOMIPP。此外，重要的是要强调，化合物 诱导的细胞死亡是明确归因于溶酶体过度胀亡，因为它与细胞凋亡、坏死或自噬不同。重要的是，当口服给予时，化合物 能有效地抑制 HeLa 异种移植模型中的肿瘤生长，而没有明显的毒性迹象。这些结果突出了 作为深入研究溶酶体过度胀亡机制的有价值工具的潜力，并作为一个有前途的先导化合物来指导结构优化。
