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Modulators of STAT Transcription Factors for the Targeted Therapy of Cancer (STAT3 Inhibitors)

Modulators of STAT Transcription Factors for the Targeted Therapy of Cancer (STAT3 Inhibitors)

F Madoux, M Koenig, H Sessions, E Nelson, BA Mercer, M Cameron, W Roush, D Frank, P Hodder

PMID: 21735601

Abstract:

The transcription factor STAT3 (signal transducer and activator of transcription 3) mediates the effects of growth factors and cytokines by regulating gene expression. In many human cancers, including breast and prostate, STAT3 is constitutively active. This leads to increased expression of genes regulating survival and proliferation, and drives the malignant behavior of these cells. As a result, the identification of novel compounds that selectively inhibit STAT3 activity may lead to useful tools to reduce cancer-associated cell proliferation, inflammation, and chemotherapeutic resistance. In this report we describe the identification of a potent and selective STAT3 inhibitor through the use of high throughput screening, synthetic medicinal chemistry, and molecular assays. The novel inhibitor (PubChem CID-2100018) belongs to the thienopyrimidine scaffold and is assigned probe number ML116 within the NIH Molecular Libraries Probe Production Center Network. Probe ML116 exhibits a STAT3 IC50 value of approximately 4 micromolar and does not inhibit the STAT1, STAT5, or NFkB signaling pathways (IC50 values greater than 56 micromolar), as determined using cell-based luciferase reporter assays. Quantitative PCR experiments demonstrated that probe ML116 inhibits transcription of the STAT3-regulated gene BCL3. In contrast, the gene A20 which is regulated by the unrelated transcription factor NF-kB, was not inhibited, further supporting the STAT3 selectivity of this probe. Whereas this compound can induce loss of viability of breast cancer cell lines such as MDA-MB-468 cells that are dependent on STAT3 activity, it displays essentially no toxicity to STAT3-independent SKBR3 breast cancer cells. Similar results were found in ovarian cancer cell lines and multiple myeloma cell lines. Due to the central role of aberrant STAT3 signaling in cancer pathogenesis, this compound may provide a useful starting point for the development of chemical scaffolds to block STAT3 signaling for cancer therapy.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP744270006	ML116		744270-00-6	Price

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