Citation

He S, Ma J, Fang Y, Liu Y, Wu S, Dong G, Wang W, Sheng C. Acta Pharmaceutica Sinica B 2021; 11(6): 1617-1628.

Copyright

(Copyright © 2021)

DOI

10.1016/j.apsb.2020.11.022

PMID

unavailable

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

Language: en

Keywords

female; controlled study; apoptosis; cell death; unclassified drug; nonhuman; animal cell; synthesis; mouse; animal experiment; binding assay; enzyme inhibitor; animal model; drug synthesis; antineoplastic agent; protein degradation; enantiomer; chemical structure; Article; in vitro study; binding affinity; in vivo study; binding competition; antineoplastic activity; proteasome; Western blotting; structure activity relation; flow cytometry; tumor volume; cancer therapy; protein p53; protein targeting; protein protein interaction; tumor xenograft; immunoblotting; non small cell lung cancer; 1,5 bis(4 (2 (4 (tert butyl) 2 ethoxyphenyl) cis 4,5 bis(4 chlorophenyl) 4,5-dihydro 1h imidazole 1 carbonyl)piperazin 1 yl) pentane 1,5 dione; 1,7 bis(4 (2 (4 (tert butyl) 2 ethoxyphenyl) cis 4,5 bis(4 chlorophenyl) 4,5 dihydro 1h imidazole 1 carbonyl)piperazin 1 yl)heptane 1,7 dione; 1,9 bis(4 (2 (4 (tert butyl) 2 ethoxyphenyl) cis 4,5 bis(4 chlorophenyl) 4,5 dihydro 1h imidazole 1 cabonyl)piperazin 1 yl) nonane 1,9 dione; 2,2' ((oxybis(ethane 2,1 diyl))bis(oxy))bis(1 (4 (2 (4 (tert butyl) 2 ethoxyphenyl) cis 4,5 bis(4 chlorophenyl) 4,5 dihydro 1h imidazole 1 carbonyl)piperazin 1 yl) ethan 1 one; 2,2' (ethane 1,2 diylbis(oxy)) bis(1 (4 (2 (4 (tert butyl) 2 ethoxyphenyl) cis 4,5 bis(4 chlorophenyl) 4,5 dihydro 1h imidazole 1 carbonyl) piperazin 1 yl) ethan 1 one; A-549 cell line; apoptosis assay; benzyloxycarbonylleucylleucylleucinal; chimeric protein; chiral chromatography; homo proteolysis targeting chimera; Homo-PROTAC; In vivo antitumor activity; MDM2; mouse double minute 2 homolog; n,n' ((ethane 1,2 diylbis(oxy))bis(ethane 2,1 diyl)) bis(2 (4 (2 (4 (tert butyl) 2 ethoxyphenyl) cis 4,5 bis(4 chlorophenyl) 4,5 dihydro 1h imidazole 1 carbonyl) 2 oxopiperazin 1 yl)acetamide); n,n' (oxybis(ethane 2,1 diyl))bis(2 (4 (2 (4 (tert butyl) 2 ethoxyphenyl) cis 4,5 bis(4 chlorophenyl) 4,5 dihydro 1h imidazole 1 carbonyl) 2 oxopiperazin 1 yl)acetamide; n.n' (((oxybis(ethane 2,1 diyl))bis(oxy))bis(ethane 2,1 diyl))bis(2 (4 (2 (4 (tert butyl) 2 ethoxyphenyl) cis 4,5 bis(4 chlorophenyl) 4,5 dihdyro 1h imidazole 1 carbonyl) 2 oxopiperazin 1 yl)acetamide); nonane 1,9 diylbis(piperazine 4,1 diyl)) bis((2 (4 (tertbutyl) 2 ethoxyphenyl) cis 4,5 bis(4 chlorophenyl) 4,5 dihydro 1h imidazole 1 yl) methanone; nonane 1,9 diylbis(piperazine 4,1 diyl))bis((2 (4 (tertbutyl) 2 ethoxyphenyl) cis 4,5 bis(4 chlorophenyl) 4,5 dihydro 1h imidazole 1 yl)methanone; optical rotation; Self-degradation; ubiquitin protein ligase E3