Discovery and characterization of a novel inhibitor of CDC25B, LGH00045.
OBJECTIVE
Cell division cycle 25 (CDC25) phosphatases have recently been considered as potential targets for the development of new cancer therapeutic agents. We aimed to discover novel CDC25B inhibitors in the present study.


METHODS
A molecular level high-throughput screening (HTS) assay was set up to screen a set of 48000 pure compounds.


RESULTS
HTS, whose average Z' factor is 0.55, was finished and LGH00045, a mixed-type CDC25B inhibitor with a novel structure and relative selectivity for protein tyrosine phosphatases, was identified. Furthermore, LGH00045 impaired the proliferation of tumor cells and increased cyclin-dependent kinase 1 inhibitory tyrosine phosphorylation. In synchronized HeLa cells, LGH00045 delayed cell cycle progression at the G2-M transition.


CONCLUSIONS
LGH00045, a novel CDC25B inhibitor identified through HTS, showed good inhibition on the proliferation of tumor cells and affected the cell cycle progression, which makes it a good hit for further structure modification.
Feng
Xu
X
College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
Wang
Li-na
LN
Zhou
Yue-yang
YY
Yu
Hai-ping
HP
Shen
Qiang
Q
Zang
Yi
Y
Zhou
Yu-bo
YB
Li
Jing-ya
JY
Zhang
Hai-xia
HX
Li
Jia
J
D016203:CDC2 Protein Kinase / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D010957:Plasmids / Q000235:genetics; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D016203:CDC2 Protein Kinase; D020687:cdc25 Phosphatases