5.09911

RNA Polymerase I Inhibitor II, BMH-21

• Synonym(s): RNA Polymerase I Inhibitor II, BMH-21, BMH21, rRNA Transcription Inhibitor II, N-(2-(Dimethylamino)ethyl)-12-oxo-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carboxamide, N-(2-(Dimethylamino)ethyl)-12-oxo-12H-benzo[g]pyrido[2,1-b]quinazoline-4-carboxamide, BMH21, rRNA Transcription Inhibitor II
• Empirical Formula (Hill Notation): C₂₁H₂₀N₄O₂
• CAS Number: 896705-16-1
• Molecular Weight: 360.41
• UNSPSC Code: 12352200
• NACRES: NA.77

Properties

• Assay: ≥98% (HPLC)
• Quality Level: 100
• form: powder
• manufacturer/tradename: Calbiochem^®
• storage condition: OK to freeze; protect from light
• color: orange-yellow
• solubility: DMSO: 1 mg/mL; 5% acetic acid: 25 mg/mL
• storage temp.: 2-8°C

Description

General description

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.

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.

Biochem/physiol Actions

Cell permeable: yes

Primary Target
rDNA

Reversible: yes

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Reconstitution

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

Other Notes

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

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

Legal Information

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

Safety Information

• Pictograms: GHS07
• Signal Word: Warning
• Hazard Statements: H302
• Precautionary Statements: P264 - P270 - P301 + P312 - P501
• Hazard Classifications: Acute Tox. 4 Oral
• Storage Class Code: 11 - Combustible Solids
• WGK: WGK 3
• Flash Point(F): Not applicable
• Flash Point(C): Not applicable