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c-MYC G-quadruplex Binding by the RNA Polymerase I Inhibitor BMH-21 and Analogues Revealed by a Combined NMR and Biochemical Approach

c-MYC G-quadruplex Binding by the RNA Polymerase I Inhibitor BMH-21 and Analogues Revealed by a Combined NMR and Biochemical Approach

Loana Musso, Stefania Mazzini, Anna Rossini, Lorenzo Castagnoli, Leonardo Scaglioni, Roberto Artali, Massimo Di Nicola, Franco Zunino, Sabrina Dallavalle

Biochim Biophys Acta Gen Subj. 2018 Mar;1862(3):615-629.

PMID: 29229300

Abstract:

Background:
Pyridoquinazolinecarboxamides have been reported as RNA polymerase I inhibitors and represent a novel class of potential antitumor agents. BMH-21, was reported to intercalate with GC-rich rDNA, resulting in nucleolar stress as a primary mechanism of cytotoxicity.
Methods:
The interaction of BMH-21 and analogues with DNA G-quadruplex structures was studied by NMR and molecular modelling. The cellular response was investigated in a panel of human tumor cell lines and protein expression was examined by Western Blot analysis.
Results and conclusions:
We explored the ability of BMH-21 and its analogue 2 to bind to G-quadruplex present in the c-MYC promoter, by NMR and molecular modelling studies. We provide evidence that both compounds are not typical DNA intercalators but are effective binders of the tested G-quadruplex. The interaction with c-MYC G-quadruplex was reflected in down-regulation of c-Myc expression in human tumor cells. The inhibitory effect was almost complete in lymphoma cells SUDHL4 characterized by overexpression of c-Myc protein. This downregulation reflected an early and persistent modulation of cMyc mRNA. Given the relevance of c-MYC in regulation of ribosome biogenesis, it is conceivable that the inhibition of c-MYC contributes to the perturbation of nuclear functions and RNA polymerase I activity. Similar experiments with CX-5461, another RNA polymerase I transcription inhibitor, indicate the same behaviour in G-quadruplex stabilization.
General significance:
Our results support the hypothesis that BMH-21 and analogue compounds share the same mechanism, i.e. G-quadruplex binding as a primary event of a cascade leading to inhibition of RNA polymerase I and apoptosis.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP896705161	BMH-21		896705-16-1	Price

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