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

Author: Shipeng HE ¹ ; Junhui MA ² ; Yuxin FANG ² ; Ying LIU ¹ ; Shanchao WU ² ; Guoqiang DONG ² ; Wei WANG ³ ; Chunquan SHENG ²
Author Information

1. Institute of Translational Medicine, Shanghai University, Shanghai 200444, China.
2. School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
3. Department of Pharmacology and Toxicology and BIO5 Institute, University of Arizona, Tucson, AZ 85721, USA.
Publication Type:Journal Article
Keywords: Homo-PROTAC; In vivo antitumor activity; MDM2; Self-degradation
From: Acta Pharmaceutica Sinica B 2021;11(6):1617-1628
CountryChina
Language:English
Abstract: 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