Small Molecules Simultaneously Inhibiting p53-Murine Double Minute 2 (MDM2) Interaction and Histone Deacetylases (HDACs): Discovery of Novel Multitargeting Antitumor Agents

被引：4

作者：

He, Shipeng ^{[1
]}

Dong, Guoqiang ^{[2
]}

Wu, Shanchao ^{[2
]}

Fang, Kun ^{[1
]}

Miao, Zhenyuan ^{[2
]}

Wang, Wei ^{[1
,3
]}

Sheng, Chunquan ^{[2
]}

机构：

[1] East China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China

[2] Second Mil Med Univ, Sch Pharm, Dept Med Chem, 325 Guohe Rd, Shanghai 200433, Peoples R China

[3] Univ New Mexico, Dept Chem & Chem Biol, MSCO3 2060, Albuquerque, NM 87131 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2018年 / 61卷 / 16期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

PROTEIN-PROTEIN INTERACTION; SUBEROYLANILIDE HYDROXAMIC ACID; T-CELL LYMPHOMA; P53; PATHWAY; VALPROIC ACID; SOLID TUMORS; HUMAN CANCER; DESIGN; ACTIVATION; APOPTOSIS;

D O I：

10.1021/acs.jmedchem.8b0064

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

p53-Murine double minute 2 (MDM2) interaction and histone deacetylases (HDACs) are important targets in antitumor drug development. Inspired by the synergistic effects between MDM2 and HDACs, the first MDM2/HDACs dual inhibitors were identified, which showed excellent activities against both targets. In particular, compound 14d was proven to be a potent and orally active MDM2/HDAC dual inhibitor, whose antitumor mechanisms were validated in cancer cells. Compound 14d showed excellent in vivo antitumor potency in the A549 xenograft model, providing a promising lead compound for the development of novel antitumor agents. Also, this proof-of concept study offers a novel and efficient strategy for multitargeting antitumor drug discovery.

引用

页码：7245 / 7260

页数：16

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