Main content area

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.