本帖最后由 StephenW 于 2012-3-19 16:18 编辑
Antiproliferative small-molecule inhibitors of transcription factor LSF reveal oncogene addiction to LSF in hepatocellular carcinoma - Trevor J. Granta,1,
- Joshua A. Bishopb,1,2,
- Lisa M. Christadoreb,
- Girish Barota,
- Hang Gyeong Chinc,d,
- Sarah Woodsona,
- John Kavourisb,
- Ayesha Siddiqe,
- Rachel Gredlere,
- Xue-Ning Shene,
- Jennifer Shermana,f,
- Tracy Meehana,
- Kevin Fitzgeraldf,
- Sriharsa Pradhand,
- Laura A. Briggsg,
- William H. Andrewsg,
- Devanand Sarkare,
- Scott E. Schausb, and
- Ulla Hansena,c,3
- Author Affiliations - Departments of aBiology and
- bChemistry, Center for Chemical Methodology and Library Development at Boston University, and
- cProgram in Molecular Biology, Cell Biology, and Biochemistry, Boston University, Boston MA 02215;
- dNew England BioLabs, Inc., Ipswich, MA 01938;
- eDepartment of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298;
- fAlnylam Pharmaceuticals, Inc., Cambridge, MA 02142; and
- gSierra Sciences, LLC, Reno, NV 89502
-
Edited by Jonathan R. Hart, The Scripps Research Institute, La Jolla, CA, and accepted by the Editorial Board January 31, 2012 (received for review January 3, 2012)
Abstract Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Despite the prevalence of HCC, there is no effective, systemic treatment. The transcription factor LSF is a promising protein target for chemotherapy; it is highly expressed in HCC patient samples and cell lines, and promotes oncogenesis in rodent xenograft models of HCC. Here, we identify small molecules that effectively inhibit LSF cellular activity. The lead compound, factor quinolinone inhibitor 1 (FQI1), inhibits LSF DNA-binding activity both in vitro, as determined by electrophoretic mobility shift assays, and in cells, as determined by ChIP. Consistent with such inhibition, FQI1 eliminates transcriptional stimulation of LSF-dependent reporter constructs. FQI1 also exhibits antiproliferative activity in multiple cell lines. In LSF-overexpressing cells, including HCC cells, cell death is rapidly induced; however, primary or immortalized hepatocytes are unaffected by treatment with FQI1. The highly concordant structure–activity relationship of a panel of 23 quinolinones strongly suggests that the growth inhibitory activity is due to a single biological target or family. Coupled with the striking agreement between the concentrations required for antiproliferative activity (GI50s) and for inhibition of LSF transactivation (IC50s), we conclude that LSF is the specific biological target of FQIs. Based on these in vitro results, we tested the efficacy of FQI1 in inhibiting HCC tumor growth in a mouse xenograft model. As a single agent, tumor growth was dramatically inhibited with no observable general tissue cytotoxicity. These findings support the further development of LSF inhibitors for cancer chemotherapy.
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发表于 2012-3-19 16:14
Scientists have identified a new compound that rapidly kills hepatocellular carcinoma (HCC) cells, the most common form of liver cancer and fifth most common cancer worldwide, while sparing healthy tissue. The compound, Factor Qunolinone Inhibitor 1 (FQI1), works by inhibiting an oncogene originally discovered by a team of researchers led by Devanand Sarkar, M.B.B.S., Ph.D., Harrison Scholar at 
