RNA Polymerase I Inhibitor II, BMH-21

Cell permeable: yes

Primary Target
rDNA

Reversible: yes

Toxicity: Standard Handling (A)

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/IC_max = 60 nM/≤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.

Peltonen, K., et al. 2014. Cancer Cell25, 77.

Peltonen, K., et al. 2010. PLoS One5, e12996.

Packaged under inert gas

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany