Zurück zu Ihrem Suchergebnis

Beschreibung

A cell-permeable, reversible DNA-intercalating benzopyridoquinazoline-carboxamide that preferentially targets GC-rich sequence, notably that of rDNA (162% of average human genome GC content), and effectively inhibits RNA polymerase I- (Pol I) mediated rDNA transcription both in cell-free assays and in cultures (IC50/ICmax = 60 nM/&le,1 M against 2-h de novo 47S transcription in A375 cells) without affecting the maturation/processing of 47S into 32S and 18S rRNA. Time-dependent studies in 1 M BMH-21-treated A375 cells reveal fast inhibition of nuclear RNA synthesis (FUrd incorporation) within 15 min, followed by progressive altered localization of nucleolar proteins (starting in <,20 min), including Pol I subunit RPA194 capping structure formation, indicative of stalled Pol I complex, and eventual proteasome-mediated RPA194 degradation (>,1 h). Although BMH-21 activates p53 independent of DNA damage-sensing ATM pathway signaling in A375 cultures, wt p53 is not a prerequisite for BMH-21 anticancer activity (Av GI50 = 110 nM/wt and 205 nM/mutant among NCI60 cancer panel). Intraperitoneal injection is demonstrated to be efficacious in suppressing A375 (25 & 50 mg/kg/d, 6d/wk) and HCT-116 (50 mg/kg/d, 7 d/wk) tumor growth in mice in vivo. MG-132 (Cat. Nos. 474790, 474787, 474788, and 474791) effectively prevents BMH-21-induced RPA194 degradation without restoring stalled rRNA synthesis., A cell-permeable, non-toxic, benzopyridoquinazoline-carboxamide compound that blocks the growth and viability of a variety of cancer cell lines (GI50 = 160 nM in NCI-60 cells), but does not significantly affect normal cells (~90-fold therapeutic window). Preferentially binds to the GC-rich DNA and inhibits RNA polymerase I (Pol I) transcription. Although it intercalates with DNA, it does not activate the DNA damage response. Induces a proteasome-dependent destruction of large Pol I catalytic subunit RPA194, independent of TP53 genetic status of cancer cells, leading to disassembly of Pol I holocomplex from the rDNA. However, it does not affect Rpb1, the large subunit of RNA polymerase II and Pol I preinitiation complex proteins. Effectively reduces the growth of A375 and HCT116 xenografts in athymic NCr nu/nu mice (50 mg/kg, i.p, 2 weeks).Please note that the molecular weight for this compound is batch-specific due to variable water content.