通过增强DDB1和PHGDH之间的相互作用，分子胶触发了PHGDH的降解
Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH
影响因子:14.60000
分区:医学1区 Top / 药学1区
发表日期:2024 Sep
作者:
Ziqi Huang, Kun Zhang, Yurui Jiang, Mengmeng Wang, Mei Li, Yuda Guo, Ruolin Gao, Ning Li, Chenyang Wang, Jia Chen, Jiefu Wang, Ning Liu, Xiang Liu, Shuangwei Liu, Mingming Wei, Cheng Yang, Guang Yang
摘要
癌症干细胞（CSC）在肿瘤起始，增殖，转移，耐药性和复发中起关键作用。因此，靶向CSC已成为癌症治疗的有前途的途径。最近，已确定3-磷酸甘油酸脱氢酶（PHGDH）与调节众多癌症干细胞的调节相关。但是，详细介绍PHGDH功能调节剂的报告可以减轻癌症类型的干性。在这项研究中，鉴定出了新型的“分子胶” LXH-3-71，并强烈诱导了PHGDH的降解，从而调节了体外和体内结直肠癌细胞（CRC）的干性。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铅化合物的抗CSC机制，而且还表明，PHGDH的降解可能比PHGDH抑制剂的开发更可行。此外，将复合LXH-3-71作为DDB1-CRL E3连接酶的新型配体，促进了针对EGFR和CDK4降解的新Protac分子的发展。
Abstract
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 in vitro and in vivo. 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.