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A Small-Molecule E2F Inhibitor Blocks Growth in a Melanoma Culture Model

A Small-Molecule E2F Inhibitor Blocks Growth in a Melanoma Culture Model

Yihong Ma, Courtney A Kurtyka, Sandhya Boyapalle, Shen-Shu Sung, Harshani Lawrence, Wayne Guida, W Douglas Cress

Cancer Res. 2008 Aug 1;68(15):6292-9.

PMID: 18676853

Abstract:

HLM006474 was identified using a computer-based virtual screen and the known crystal structure of the DNA-bound E2F4/DP2 heterodimer. Treatment of multiple cell lines with HLM006474 resulted in the loss of intracellular E2F4 DNA-binding activity as measured by electrophoretic mobility shift assay within hours. Overnight exposure to HLM006474 resulted in down-regulation of total E2F4 protein as well as known E2F targets. The effects of HLM006474 treatment on different cell lines varied but included a reduction in cell proliferation and an increase in apoptosis. HLM006474 induced apoptosis in a manner distinct from cisplatin and doxorubicin. E2F4-null mouse embryonic fibroblasts were less sensitive than wild-type counterparts to the apoptosis-inducing activity of the compound, revealing its biological specificity. A375 cells were extremely sensitive to the apoptosis-inducing activity of the compound in two-dimensional culture, and HLM006474 was a potent inhibitor of melanocytes proliferation and subsequent invasion in a three-dimensional tissue culture model system. Together, these results suggest that interference with E2F activity using small molecules may have clinical application in cancer therapy.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP353519638	HLM006474		353519-63-8	Price

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