Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts

Abstract

Computer-aided lead optimization derives a unique, orally bioavailable inhibitor of the signal transducer and activator of transcription (Stat)3 Src homology 2 domain. BP-1-102 binds Stat3 with an affinity ( K D ) of 504 nM, blocks Stat3–phospho-tyrosine (pTyr) peptide interactions and Stat3 activation at 4–6.8 μM, and selectively inhibits growth, survival, migration, and invasion of Stat3-dependent tumor cells. BP-1-102–mediated inhibition of aberrantly active Stat3 in tumor cells suppresses the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, VEGF, and Krüppel-like factor 8, which is identified as a Stat3 target gene that promotes Stat3-mediated breast tumor cell migration and invasion. Treatment of breast cancer cells with BP-1-102 further blocks Stat3–NF-κB cross-talk, the release of granulocyte colony-stimulating factor, soluble intercellular adhesion molecule 1, macrophage migration-inhibitory factor/glycosylation-inhibiting factor, interleukin 1 receptor antagonist, and serine protease inhibitor protein 1, and the phosphorylation of focal adhesion kinase and paxillin, while enhancing E-cadherin expression. Intravenous or oral gavage delivery of BP-1-102 furnishes micromolar or microgram levels in tumor tissues and inhibits growth of human breast and lung tumor xenografts.

IL-17A/IL-17RA interaction promoted metastasis of osteosarcoma cells

“…22 IL-17A had recently been reported to stimulate Stat3 activation through a positive feedback loop in inflammatory cells, fibroblasts, as well as the growth of B16 melanoma and MB49 bladder carcinoma. 27 As Stat3 activation in tumor cells and tumor-associated inflammatory cells played a critical role in tumor progression by augmenting tumor survival and tumor angiogenesis, and suppressing antitumor immunity, [24][25][26] we therefore detected the Stat3 activity in OS cells in response to IL-17A/IL-17RA interaction. Indeed, here we found that IL-17A/IL-17RA interaction could effectively induce the Stat3 activation in OS cells.…”

“…It is well acknowledged that Stat3 activation in tumor cells and tumor-associated inflammatory cells played a critical role in tumor progression by augmenting tumor survival and tumor angiogenesis, and suppressing antitumor immunity. [24][25][26] Recent study showed that IL-17A could stimulate Stat3 activation in B16 melanoma and MB49 bladder carcinoma cells. 27 We therefore determined whether the IL-17A/IL-17RA interaction could promote the Stat3 activity in OS cells.…”

Indirubin Derivative 6BIO Suppresses Metastasis

“…Furthermore, because STAT3 is constitutively active in the majority of highly invasive cancer types, inhibition of tyrosine kinase pathways mediating STAT3 activation might be a promising therapeutic option for treatment of metastatic cancers (39). Indeed, blocking of STAT3 signaling cascades using small-molecule inhibitors suppresses migration and invasion of breast cancer cells (40). Liu and colleagues showed that 6BIO is a pan-JAK inhibitor and thus induces apoptosis in melanoma cells (27).…”

Low PIAS3 Expression in Malignant Mesothelioma Is Associated with Increased STAT3 Activation and Poor Patient Survival

“…These results indicate that downstream effectors of tyrosine kinase receptor signaling such as STATs may represent a more attractive choice for drug targeting because they represent an integration point for multiple oncogenic signaling pathways. Unfortunately, specific and effective STAT3 inhibitors are still only in early development, although promising lead compounds have recently been reported (33).…”