Oncrasin 1

Oncrasin 1 is a small molecule antitumor agent with IC50 value of 4.81 μM [1].
The activated mutations of Ras genes (K-Ras, N-Ras and H-Ras) play important roles in tumorigenesis and maintenance of malignant phenotypes. The mutations make Ras constitutively be in the activated state with GTP-bound. Among the three Ras genes, the mutations of K-Ras are the most frequently found in tumors and are associated with resistance to radio therapy, chemotherapy and poor prognosis. Thus, mutant K-Ras is important target for antitumor treatment. Oncrasin 1 is a small-molecule compound that found by a synthetic lethality screening. It effectively killed tumor cells with K-Ras mutation but not normal isogenic cells through inducing cell apoptosis. Besides that, Oncrasin 1 caused abnormal aggregation of PKCι of those sensitive cells [1].
In a sulforhodamine B (SRB) assay, treatment of Oncrasin 1 at final concentration of 5 μg/ml killed more than 50% of cells. Oncrasin 1 was highly selective against K-Ras mutation, it showed dose-dependent cytotoxicity in T29Kt1 (K-Ras mutant) cells with IC50 value of 4.81 μM. For T29Ht1 (H-Ras mutant) cells and T29 (wild-type Ras) cells, Oncrasin 1 showed no cytotoxicity even at concentration of 33 μM. For the other K-Ras-mutant tumor cells such as A549, H2122 and H460, Oncrasin 1 all showed cytotoxicity with IC50 value of ≤ 3 μM. It was found that induction of apoptosis was a major mechanism of Oncrasin 1 treatment [1].
In mice injected with H460 cells, administration of Oncrasin 1 at dose of 100 mg/kg resulted in significant tumor growth suppression by 75.4%. In addition, the survival time was prolonged by the Oncrasin 1 treatment [1].
Reference:
[1] Guo W, Wu S, Liu J, et al. Identification of a small molecule with synthetic lethality for K-ras and protein kinase C iota. Cancer research, 2008, 68(18): 7403-7408.

Analogues and derivatives of oncrasin-1, a novel inhibitor of the C-terminal domain of RNA polymerase II and their antitumor activities.[Pubmed:21443218]

J Med Chem. 2011 Apr 28;54(8):2668-79.

To optimize the antitumor activity of oncrasin-1, a small molecule RNA polymerase II inhibitor, we evaluated 69 oncrasin-1 analogues for their cytotoxic activity against normal human epithelial cells and K-Ras mutant tumor cells. About 40 of those compounds were as potent as or more potent than oncrasin-1 in tumor cells and had a minimal cytotoxic effect on normal cells. Structure-activity relationship analysis revealed that most of the active compounds contained either a hydroxymethyl group or an aldehyde group as a substitute at the 3-position of the indole. Both electron-donating and electron-withdrawing groups in the benzene ring were well tolerated. The hydroxymethyl compounds ranged from equipotent with to 100 times as potent as the corresponding aldehyde compounds. We tested three active analogues' effect on RNA polymerase phosphorylation and found that they all inhibited phosphorylation of the C-terminal domain of RNA polymerase II, suggesting that the active compounds might act through the same mechanisms as oncrasin-1.

Interruption of RNA processing machinery by a small compound, 1-[(4-chlorophenyl)methyl]-1H-indole-3-carboxaldehyde (oncrasin-1).[Pubmed:19208825]

Mol Cancer Ther. 2009 Feb;8(2):441-8.

Protein kinase Ciota (PKCiota) is activated by oncogenic Ras proteins and is required for K-Ras-induced transformation and colonic carcinogenesis in vivo. However, the role of PKCiota in signal transduction and oncogenesis is not clear. We recently identified a small molecule, designated 1-[(4-chlorophenyl)methyl]-1H-indole-3-carboxaldehyde (oncrasin-1), that can selectively kill K-Ras mutant cancer cells and induce abnormal nuclear aggregation of PKCiota in sensitive cells but not in resistant cells. To determine the causes and biological consequences of PKCiota aggregates in the nucleus, we analyzed the effect of oncrasin-1 on proteins involved in DNA repair and RNA processing. Our results showed that oncrasin-1 treatment led to coaggregation of PKCiota and splicing factors into megaspliceosomes but had no obvious effects on the DNA repair molecule Rad51. Moreover, oncrasin-1 treatment suppressed the phosphorylation of the largest subunit of RNA polymerase II and the expression of intronless reporter genes in sensitive cells but not in resistant cells, suggesting that suppression of RNA transcription is a major effect of oncrasin-1 treatment. Studies with cultured cells or with recombinant proteins showed that oncrasin-1 can disrupt the interaction of PKCiota and cyclin-dependent protein kinase 9/cyclin T1 complex, which is known to phosphorylate the largest subunit of RNA polymerase II and is required for RNA transcription. Together, our results suggest that oncrasin-1 suppresses the function of RNA processing machinery and that PKCiota might be involved in the biological function of RNA processing complexes.

Oncrasin-1 is a potent and effective anticancer inhibitor that kills various human lung cancer cells with K-Ras mutations at low or submicromolar concentrations; also led to abnormal aggregation of PKCι in nucleus of sensitive cells but not in resistant cells.

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