分子胶促使DDB1与PHGDH相互作用增强，从而诱导PHGDH降解以靶向癌症干细胞

Molecular glue triggers degradation of PHGDH by enhancing the interaction between DDB1 and PHGDH

Acta Pharmaceutica Sinica B

影响因子:14.6

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

DOI: 10.1016/j.apsb.2024.06.001

摘要

癌症干细胞（CSCs）在肿瘤的发生、增殖、转移、耐药和复发中发挥关键作用。因此，靶向CSC已成为癌症治疗的一个有前景的途径。近年来，3-磷酸甘油酰胺脱氢酶（PHGDH）被发现与多种癌症干细胞的调控密切相关。然而，调控PHGDH功能的因子及其在减弱癌细胞干性方面的研究有限。本研究中，发现一种新型“分子胶”LXH-3-71，能强烈诱导PHGDH的降解，调节结直肠癌（CRC）细胞的干性。在体内外实验中，LXH-3-71表现出能在PHGDH与DDB1-CRL E3连接酶之间形成动态嵌合体的能力。这些发现不仅阐明了该先导化合物的抗CSC机制，也提示PHGDH的降解可能比开发PHGDH抑制剂更具潜力。同时，LXH-3-71还作为DDB1-CRL E3连接酶的新配体，有助于开发针对EGFR和CDK4降解的新型PROTAC分子。

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.