Structure-Activity Relationships and Cancer-Cell Selective Toxicity of Novel Inhibitors of Glioma-Associated Oncogene Homologue 1 (Gli1) Mediated Transcription

被引：23

作者：

Mahindroo, Neeraj ^{[1
]}

Connelly, Michele C. ^{[1
]}

Punchihewa, Chandanamali ^{[1
]}

Kimura, Hiromichi ^{[2
]}

Smeltzer, Matthew P. ^{[3
]}

Wu, Song ^{[3
]}

Fujii, Naoaki ^{[1
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Dept Dev Neurobiol, Memphis, TN 38105 USA

[3] St Jude Childrens Res Hosp, Dept Biostat, Memphis, TN 38105 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 14期

关键词：

HEDGEHOG PATHWAY; SUPPRESSOR; DEFECTS; GROWTH; GENE;

D O I：

10.1021/jm900106f

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We report novel inhibitors of Gli1-mediated transcription as potential anticancer agents. Focused chemical libraries were designed and assessed for inhibition of functional cell-based Gli1-mediated transcription and selective toxicity toward cancer cells. The SAR was revealed, and the selectivity of the lead compounds' inhibition of Gli1-mediated transcription over that of Gli2 was determined. Compound 63 (NMDA298-1), which inhibited Gli1-mediated transcription in C3H10T1/2 cells with all IC50 of 6.9 mu M, showed 3-fold selectivity for inhibiting transcription mediated by Gli1 over that by Gli2. Cell-viability assays were performed to evaluate the chemical library in a normal cell line and a panel of cancer cell lines with or without up-regulated expression of the Gli1 gene. These compounds decreased the viability of several cancer cell lines but were less active in the noncancerous BJ-hTERT cells.

引用

页码：4277 / 4287

页数：11

共 34 条

[31] Inhibition of prostate cancer proliferation by interference with SONICHEDGEHOG-GLI1 signaling [J].

Sanchez, P ;

Hernández, AM ;

Stecca, B ;

Kahler, AJ ;

DeGueme, AM ;

Barrett, A ;

Beyna, M ;

Datta, MW ;

Datta, S ;

Altaba, ARI .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (34) :12561-12566

[32] Shh pathway activity is down-regulated in cultured medulloblastoma cells: Implications for preclinical studies [J].

Sasai, K ;

Romer, JT ;

Lee, Y ;

Finkelstein, D ;

Fuller, C ;

McKinnon, PJ ;

Curran, T .

CANCER RESEARCH, 2006, 66 (08) :4215-4222

[33]

Sasaki H, 1997, DEVELOPMENT, V124, P1313

[34]

Stecca Barbara, 2002, J Biol, V1, P9, DOI 10.1186/1475-4924-1-9

← 1 2 3 4 →