Selective inhibition of EZH2 by ZLD10A blocks H3K27 methylation and kills mutant lymphoma cells proliferation.
EZH2 (Enhancer of zeste homolog 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2), which is involved in repressing gene expression by methylating lysine 27 of histone H3 (H3K27) and regulates cell proliferation. EZH2 overexpression is implicated in tumorigenesis and has been a candidate oncogene in several tumor types. Recently, point mutations of EZH2 at Tyr641 and Ala677 were identified in diffuse large B cell lymphoma and follicular lymphoma, where they drive H3K27 hypertrimethylation and cancer progression. Here, we reported a novel, highly potent and selective small molecule inhibitor of EZH2, ZLD10A, which inhibited wild-type and mutant versions of EZH2 with nanomolar potency and had greater than 1000-fold selectivity against 10 other histone methyltransferases. Our results have shown that the compound suppressed global H3K27 methylation and cause the anti-proliferation effects in a concentration- and time-dependent manner in DLBCL cell lines. These results demonstrated that ZLD10A, as a novel EZH2 inhibitor, could be a potential promising agent for the treatment of EZH2 mutant lymphoma.
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Xuejiao
X
Song
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: zhangxiaoxu0510@163.com.
Lidan
L
Zhang
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Tiantao
T
Gao
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Tinghong
T
Ye
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Yongxia
Y
Zhu
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Qian
Q
Lei
College of Chemistry and Life Science, Chengdu Normal University, Chengdu 611130, China.
Qiang
Q
Feng
College of Chemistry and Life Science, Chengdu Normal University, Chengdu 611130, China.
Bing
B
He
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Hongxia
H
Deng
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China. Electronic address: yuluot@scu.edu.cn.
Luoting
L
Yu
D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000494:pharmacology*; D008223:Lymphoma / Q000473:pathology*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D009154:Mutation / Q000235:genetics*
D001549:Benzamides; D006657:Histones; D007546:Isoquinolines; C000613814:ZLD10A compound; D000076983:Histone Methyltransferases; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine
Anti-tumor; EZH2; Lymphoma; Small molecule