STAT Inhibitor

Signal transducer and activators of transcription (STATs) proteins, comprise of a 7-member family of transcription factors induced by tyrosine phosphorylation under the stimulation of cytokines, hormones, and growth factors. Regulating cell growth by modulating the expression of specific target genes, aberrant STAT activation is also strongly suspected in cancer. STAT oncogenic transcriptional roles include cell progression, differentiation, suppression of anti-tumor immunity, and promotion of survival through anti-apoptotic effects. Constitutive STAT activity is especially noted in colorectal, myeloma, pancreatic, ovarian, liver, breast, prostate, lung, several forms of leukemia and lymphoma, in addition to other solid and hematological cancers.

Elevated levels of STAT3 and STAT5 phosphorylation correlate with tumor invasion, metastasis, and worse prognosis in many different cancers. Interruption of constitutively activated STAT members, notably STAT3 and STAT5, is sufficient to block cells from undergoing malignant transformation. Blocking STAT3 signaling in carcinoma cells by STAT3 antisense oligonucleotides, STAT3 small interfering RNAs (siRNAs), or stable transfection of dominant-negative STAT3 have been shown to inhibit cancer cells growth and induce apoptosis. Agents which inhibit JAK2, a kinase phosphorylating STAT3, suppress growth, decrease invasion of carcinoma cells, and induce apoptosis. These findings support constitutive STAT signaling are crucial to the survival, invasion, and growth of human carcinoma cells.

Targeting downstream mediators of tyrosine kinase via inhibition of STAT3 and STAT5 offers a more direct treatment strategy for cancer, especially tumors refractory to tyrosine kinase blocking agents. Cancers resistant to kinase inhibitor therapies, (eg. EGFR inhibitors), may be due to elevated STAT activity via non-EGF dependent signals. Findings suggest limited efficacy and high toxicity potential is associated with blocking multifunctional kinases, such as JAKs, in aiming to prevent down-stream signaling events mediated by other oncogenic activators, (eg. Src Kinases, MAPK, C-MET), or other inducers of STAT3 phosphorylation. Therefore, direct inhibition of STAT3 and STAT5 function represents a more targeted intervention to eliminate malignant transformation and cancer cell growth, but also represents an approach which maintains normal upstream kinase functions essential for healthy cellular function.


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