@article{ref1,
title="Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer",
journal="Acta Pharmaceutica Sinica B",
year="2021",
author="He, S. and Ma, J. and Fang, Y. and Liu, Y. and Wu, S. and Dong, G. and Wang, W. and Sheng, C.",
volume="11",
number="6",
pages="1617-1628",
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 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. © 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences<p /><p>Language: en</p>",
language="en",
issn="2211-3835",
doi="10.1016/j.apsb.2020.11.022",
url="http://dx.doi.org/10.1016/j.apsb.2020.11.022"
}