Cancer stem cells (CSCs) play a pivotal role in tumor initiation, proliferation, metastasis, drug resistance, and recurrence. Consequently, targeting CSCs has emerged as a promising avenue for cancer therapy. Recently, 3-phosphoglycerate dehydrogenase (PHGDH) has been identified as being intricately associated with the regulation of numerous cancer stem cells. Yet, reports detailing the functional regulators of PHGDH that can mitigate the stemness across cancer types are limited. In this study, the novel “molecular glue” LXH-3-71 was identified, and it robustly induced degradation of PHGDH, thereby modulating the stemness of colorectal cancer cells (CRCs) both and . Remarkably, LXH-3-71 was observed to form a dynamic chimera, between PHGDH and the DDB1-CRL E3 ligase. These insights not only elucidate the anti-CSCs mechanism of the lead compound but also suggest that degradation of PHGDH may be a more viable therapeutic strategy than the development of PHGDH inhibitors. Additionally, compound LXH-3-71 was leveraged as a novel ligand for the DDB1-CRL E3 ligase, facilitating the development of new PROTAC molecules targeting EGFR and CDK4 degradation.

中文翻译：

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分子胶通过增强 DDB1 和 PHGDH 之间的相互作用触发 PHGDH 降解


癌症干细胞（CSC）在肿瘤发生、增殖、转移、耐药和复发中发挥着关键作用。因此，靶向 CSC 已成为癌症治疗的一种有前景的途径。最近，3-磷酸甘油酸脱氢酶 (PHGDH) 已被确定与许多癌症干细胞的调节密切相关。然而，详细介绍可减轻跨癌症类型干性的 PHGDH 功能调节剂的报告仍然有限。在这项研究中，鉴定出新型“分子胶”LXH-3-71，它能强烈诱导 PHGDH 降解，从而调节结直肠癌细胞 (CRC) 和 的干细胞性。值得注意的是，观察到 LXH-3-71 在 PHGDH 和 DDB1-CRL E3 连接酶之间形成动态嵌合体。这些见解不仅阐明了先导化合物的抗 CSC 机制，而且表明 PHGDH 的降解可能是比开发 PHGDH 抑制剂更可行的治疗策略。此外，化合物LXH-3-71被用作DDB1-CRL E3连接酶的新型配体，促进了针对EGFR和CDK4降解的新PROTAC分子的开发。