TY - JOUR
T1 - Small Molecules Simultaneously Inhibiting p53-Murine Double Minute 2 (MDM2) Interaction and Histone Deacetylases (HDACs)
T2 - Discovery of Novel Multitargeting Antitumor Agents
AU - He, Shipeng
AU - Dong, Guoqiang
AU - Wu, Shanchao
AU - Fang, Kun
AU - Miao, Zhenyuan
AU - Wang, Wei
AU - Sheng, Chunquan
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China (grants 21738002 to W.W., 81673352 to Z.M., and 81725020 to C.S.) and the National Key R&D Program of China (2017YFA0506000 to C.S.).
Publisher Copyright:
© Copyright 2018 American Chemical Society.
PY - 2018/8/23
Y1 - 2018/8/23
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85050731774
UR - https://www.scopus.com/pages/publications/85050731774#tab=citedBy
U2 - 10.1021/acs.jmedchem.8b00664
DO - 10.1021/acs.jmedchem.8b00664
M3 - Article
C2 - 30045621
AN - SCOPUS:85050731774
SN - 0022-2623
VL - 61
SP - 7245
EP - 7260
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -