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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Cancer stem cells (CSCs) drive tumor initiation, metastasis, and drug resistance.
• 3-phosphoglycerate dehydrogenase (PHGDH) is implicated in regulating CSC properties.
• Limited understanding exists regarding PHGDH regulators that can reduce cancer stemness.

Purpose of the Study:

• To identify novel regulators of PHGDH that can mitigate cancer stemness.
• To investigate the therapeutic potential of targeting PHGDH for colorectal cancer treatment.

Main Methods:

• Identification of a novel molecular glue, LXH-3-71.
• Assessment of LXH-3-71's effect on PHGDH degradation in colorectal cancer cells (CRCs) in vitro and in vivo.
• Investigation of LXH-3-71's mechanism of action, including its interaction with the DDB1-CRL E3 ligase.

Main Results:

• LXH-3-71 robustly induced PHGDH degradation, modulating CSC stemness in CRCs.
• LXH-3-71 formed a chimera between PHGDH and the DDB1-CRL E3 ligase.
• LXH-3-71 facilitated the development of PROTAC molecules targeting EGFR and CDK4.

Conclusions:

• PHGDH degradation is a viable therapeutic strategy for targeting CSCs, potentially more effective than PHGDH inhibitors.
• LXH-3-71 demonstrates significant anti-CSC activity and serves as a foundation for developing new targeted cancer therapies.