BMH-21

BMH-21 is a planar heterocyclic small molecule DNA intercalator with inhibition of Pol I activity at IC50 = 0.06 µM. [1]
DNA interaction is a well-recognized property for several classes of cancer drugs, which interact with the duplex DNA with three typical binding modalities, namely DNA intercalation, groove binding and covalent interactions. [1]
BMH-21 intercalated into dsDNA and had binding preference towards GC-rich DNA sequences. BMH-21 had wide cytotoxic activities against human cancer cell lines, and acted in p53-independent manner, widely considered as a mediator of many cytotoxic agents. BMH-21 played as a novel agent that inhibited transcription of RNA polymerase I (Pol I) by binding to ribosomal (r) DNA that caused Pol I blockade and degradation of the large catalytic subunit of Pol I, RPA194. BMH-21 led to the dissolution of the nucleolar structure. [1] BMH-21 clearly induced p53 expression in the epithelial compartment of human prostate tissues indicating tissue permeability. [2]
References:
[1]. Colis L, Peltonen K, Sirajuddin P et al. DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response. Oncotarget. 2014 Jun 30;5(12):4361-9.
[2]. Peltonen K, Colis L, Liu H et al. Identification of novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known therapeutic agents. PLoS One. 2010 Sep 27;5(9):e12996.

DNA intercalator BMH-21 inhibits RNA polymerase I independent of DNA damage response.[Pubmed:24952786]

Oncotarget. 2014 Jun 30;5(12):4361-9.

DNA intercalation is a major therapeutic modality for cancer therapeutic drugs. The therapeutic activity comes at a cost of normal tissue toxicity and genotoxicity. We have recently described a planar heterocyclic small molecule DNA intercalator, BMH-21, that binds ribosomal DNA and inhibits RNA polymerase I (Pol I) transcription. Despite DNA intercalation, BMH-21 does not cause phosphorylation of H2AX, a key biomarker activated in DNA damage stress. Here we assessed whether BMH-21 activity towards expression and localization of Pol I marker proteins depends on DNA damage signaling and repair pathways. We show that BMH-21 effects on the nucleolar stress response were independent of major DNA damage associated PI3-kinase pathways, ATM, ATR and DNA-PKcs. However, testing a series of BMH-21 derivatives with alterations in its N,N-dimethylaminocarboxamide arm showed that several derivatives had acquired the property to activate ATM- and DNA-PKcs -dependent damage sensing and repair pathways while their ability to cause nucleolar stress and affect cell viability was greatly reduced. The data show that BMH-21 is a chemically unique DNA intercalator that has high bioactivity towards Pol I inhibition without activation or dependence of DNA damage stress. The findings also show that interference with DNA and DNA metabolic processes can be exploited therapeutically without causing DNA damage.

Design, synthesis, and structure-activity relationships of pyridoquinazolinecarboxamides as RNA polymerase I inhibitors.[Pubmed:24847734]

J Med Chem. 2014 Jun 12;57(11):4950-61.

RNA polymerase I (Pol I) is a dedicated polymerase that transcribes the 45S ribosomal (r) RNA precursor. The 45S rRNA precursor is subsequently processed into the mature 5.8S, 18S, and 28S rRNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. On the basis of the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides have been evaluated as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. Structure-activity relationships in assays of nucleolar stress and cell viability demonstrate key pharmacophores and their physicochemical properties required for potent activation of Pol I stress and cytotoxicity. This work identifies a set of bioactive compounds that potently cause RPA194 degradation that function in a tightly constrained chemical space. This work has yielded novel derivatives that contribute to the development of Pol I inhibitory cancer therapeutic strategies.

A targeting modality for destruction of RNA polymerase I that possesses anticancer activity.[Pubmed:24434211]

Cancer Cell. 2014 Jan 13;25(1):77-90.

We define the activity and mechanisms of action of a small molecule lead compound for cancer targeting. We show that the compound, BMH-21, has wide and potent antitumorigenic activity across NCI60 cancer cell lines and represses tumor growth in vivo. BMH-21 binds GC-rich sequences, which are present at a high frequency in ribosomal DNA genes, and potently and rapidly represses RNA polymerase I (Pol I) transcription. Strikingly, we find that BMH-21 causes proteasome-dependent destruction of RPA194, the large catalytic subunit protein of Pol I holocomplex, and this correlates with cancer cell killing. Our results show that Pol I activity is under proteasome-mediated control, which reveals an unexpected therapeutic opportunity.

Identification of novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known therapeutic agents.[Pubmed:20885994]

PLoS One. 2010 Sep 27;5(9):e12996.

Manipulation of the activity of the p53 tumor suppressor pathway has demonstrated potential benefit in preclinical mouse tumor models and has entered human clinical trials. We describe here an improved, extensive small-molecule chemical compound library screen for p53 pathway activation in a human cancer cell line devised to identify hits with potent antitumor activity. We uncover six novel small-molecule lead compounds, which activate p53 and repress the growth of human cancer cells. Two tested compounds suppress in vivo tumor growth in an orthotopic mouse model of human B-cell lymphoma. All compounds interact with DNA, and two activate p53 pathway in a DNA damage signaling-dependent manner. A further screen of a drug library of approved drugs for medicinal uses and analysis of gene-expression signatures of the novel compounds revealed similarities to known DNA intercalating and topoisomerase interfering agents and unexpected connectivities to known drugs without previously demonstrated anticancer activities. These included several neuroleptics, glycosides, antihistamines and adrenoreceptor antagonists. This unbiased screen pinpoints interference with the DNA topology as the predominant mean of pharmacological activation of the p53 pathway and identifies potential novel antitumor agents.

BMH-21 is a small molecule DNA intercalator that binds ribosomal DNA and inhibits RNA polymerase I (Pol I) transcription; does not cause phosphorylation of H2AX.

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