TY  - JOUR
PY  - 2021//
TI  - Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer
JO  - Acta Pharmaceutica Sinica B
A1  - He, S.
A1  - Ma, J.
A1  - Fang, Y.
A1  - Liu, Y.
A1  - Wu, S.
A1  - Dong, G.
A1  - Wang, W.
A1  - Sheng, C.
SP  - 1617
EP  - 1628
VL  - 11
IS  - 6
N2  - 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>
LA  - en
SN  - 2211-3835
UR  - http://dx.doi.org/10.1016/j.apsb.2020.11.022
ID  - ref1
ER  -