Structure-activity relationships and cancer-cell selective toxicity of novel inhibitors of glioma-associated oncogene homologue 1 (Gli1) mediated transcription.
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 an IC(50) of 6.9 muM, 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.
Mahindroo
Neeraj
N
St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Connelly
Michele C
MC
Punchihewa
Chandanamali
C
Kimura
Hiromichi
H
Smeltzer
Matthew P
MP
Wu
Song
S
Fujii
Naoaki
N
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D006801:Humans; D020128:Inhibitory Concentration 50; D009369:Neoplasms / Q000473:pathology*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D014439:Tyramine / Q000737:chemistry; D000071676:Zinc Finger Protein GLI1
D000970:Antineoplastic Agents; D015513:Oncogene Proteins; D011720:Pyrazoles; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; C031280:pyrazole; D014439:Tyramine