Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer

Shipeng He, Junhui Ma, Yuxin Fang, Ying Liu, Shanchao Wu, Guoqiang Dong, Wei Wang, Chunquan Sheng

Research output: Contribution to journalArticlepeer-review

38 Scopus citations


The dose-related adverse effects of MDM2‒P53 inhibitors have caused significant concern in the development of clinical safe anticancer agents. Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2‒P53 interaction. The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53. The new homo-PROTACs are designed to induce self-degradation of MDM2. The results of the investigation have shown that PROTAC 11a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung cancer cells. Furthermore, markedly, enantiomer 11a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model, which is the first example of homo-PROTAC with in vivo therapeutic potency. This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown, which could be developed into a safe therapy for cancer treatment.

Original languageEnglish (US)
Pages (from-to)1617-1628
Number of pages12
JournalActa Pharmaceutica Sinica B
Issue number6
StatePublished - Jun 2021


  • Homo-PROTAC
  • In vivo antitumor activity
  • MDM2
  • Self-degradation

ASJC Scopus subject areas

  • Pharmacology, Toxicology and Pharmaceutics(all)


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