TY - JOUR
T1 - Design, synthesis, and biological evaluation of potent EZH2/LSD1 dual inhibitors for prostate cancer
AU - Le, Meiling
AU - Lu, Wenhua
AU - Tan, Xiaozhuo
AU - Luo, Bingling
AU - Yu, Tiantian
AU - Sun, Yameng
AU - Guo, Zhirong
AU - Huang, Peng
AU - Zhu, Daqian
AU - Wu, Qiang
AU - Ganesan, A.
AU - Wen, Shijun
N1 - Funding Information:
The authors are grateful for the grant support from Guangdong Science and Technology Program (2022A0505050034, 2023A1515011858) and National Natural Science Foundation of China (81872440).
Publisher Copyright:
© 2024 American Chemical Society.
PY - 2024/9/12
Y1 - 2024/9/12
N2 - As histone modification enzymes, EZH2 mediates H3K27 trimethylation (H3K27me3), whereas LSD1 removes methyl groups from H3K4me1/2 and H3K9me1/2. Synergistic anticancer effects of combining inhibitors of these two enzymes are observed in leukemia and prostate cancer. Thus, a series of EZH2/LSD1 dual inhibitors are designed and synthesized to evaluate their anticancer activity. After the structure-activity study, one of the best compounds, ML234, displayed excellent antiproliferative capacity against prostate cancer cell lines LNCAP, PC3, and 22RV1. Enzymatic assays ascertained that the anticancer potency of ML234 was mediated through coinhibition of EZH2 and LSD1. Moreover, the accumulation of H3K4me2 and H3K9me2 and the decrease of H3K27me3 induced by ML234 were verified by Western blot analysis. More importantly, the compound remarkably suppressed the tumor growth and enhanced the therapeutic efficacy of clinical drug enzalutamide in the 22RV1 xenograft mouse model, indicating that it may have potential as an anticancer agent in prostate cancer.
AB - As histone modification enzymes, EZH2 mediates H3K27 trimethylation (H3K27me3), whereas LSD1 removes methyl groups from H3K4me1/2 and H3K9me1/2. Synergistic anticancer effects of combining inhibitors of these two enzymes are observed in leukemia and prostate cancer. Thus, a series of EZH2/LSD1 dual inhibitors are designed and synthesized to evaluate their anticancer activity. After the structure-activity study, one of the best compounds, ML234, displayed excellent antiproliferative capacity against prostate cancer cell lines LNCAP, PC3, and 22RV1. Enzymatic assays ascertained that the anticancer potency of ML234 was mediated through coinhibition of EZH2 and LSD1. Moreover, the accumulation of H3K4me2 and H3K9me2 and the decrease of H3K27me3 induced by ML234 were verified by Western blot analysis. More importantly, the compound remarkably suppressed the tumor growth and enhanced the therapeutic efficacy of clinical drug enzalutamide in the 22RV1 xenograft mouse model, indicating that it may have potential as an anticancer agent in prostate cancer.
UR - http://www.scopus.com/inward/record.url?scp=85202753786&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.4c01250
DO - 10.1021/acs.jmedchem.4c01250
M3 - Article
C2 - 39196854
AN - SCOPUS:85202753786
VL - 67
SP - 15586
EP - 15605
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 17
ER -
