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Orally bioavailable small-molecule inhibitor of transcription factor Stat3 regresses human breast and lung cancer xenografts
- Zhang, Xiaolei, Yue, Peibin, Page, Brent D. G., Li, Tianshu, Zhao, Wei, Namanja, Andrew T., Paladino, David, Zhao, Jihe, Chen, Yuan, Gunning, Patrick T., Turkson, James
- Proceedings of the National Academy of Sciences of the United States of America 2012 v.109 no.24 pp. 9623-9628
- antagonists, breast neoplasms, cadherins, cell adhesion, cell movement, cyclins, genes, granulocyte colony-stimulating factor, human growth, humans, interleukin-1, intravenous injection, lung neoplasms, macrophages, neoplasm cells, non-specific protein-tyrosine kinase, phosphorylation, pro-apoptotic proteins, proteinase inhibitors, serine proteinases, signal transduction, tissues, transactivators, vascular endothelial growth factors
- 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.