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1.
Acta Pharmaceutica Sinica B ; (6): 1617-1628, 2021.
Article in English | WPRIM | ID: wpr-888824

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

2.
Acta Pharmaceutica Sinica B ; (6): 1294-1308, 2020.
Article in English | WPRIM | ID: wpr-828807

ABSTRACT

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent and antitumor potency. Particularly, compound was orally active and possessed excellent antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, .) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.

3.
Acta Pharmaceutica Sinica B ; (6): 144-156, 2019.
Article in English | WPRIM | ID: wpr-774995

ABSTRACT

Natural product evodiamine and its derivatives represent a promising class of multi-target antitumor agents. However, the clinical development of these compounds has been hampered by a poor understanding of their antitumor mechanisms. To tackle this obstacle, herein, novel fluorescent probes were designed to elucidate the antitumor mode of action of 10-hydroxyevodiamine. This compound was proven to be distributed in the mitochondria and lysosomes and to act by autophagy and apoptosis mechanisms.

4.
Journal of Pharmaceutical Practice ; (6): 337-341,371, 2014.
Article in Chinese | WPRIM | ID: wpr-790354

ABSTRACT

Cancer is a serious threat to human life and health .Therefore, there is an emergent need to develop novel anti-cancer agents with new structural type , new mechanism of action and higher efficacy .Natural products had played a key role in the dis-covery of anticancer agents .The anti-cancer activity , mechanism of action , structure and activity relationship of several lead-com-pounds which were derived from natural products were summarized in this review .

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