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.

• Authors: Xiaolei Zhang, Peibin Yue, Brent D G Page, Tianshu Li, Wei Zhao, Andrew T Namanja, David Paladino, Jihe Zhao, Yuan Chen, Patrick T Gunning, James Turkson
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 24 Pg. 9623-8 (Jun 12 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22623533 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• STAT3 Transcription Factor
• STAT3 protein, human

Topics

• Administration, Oral
• Animals
• Biological Availability
• Breast Neoplasms (therapy)
• Cell Line
• Cell Line, Tumor
• Female
• Humans
• Lung Neoplasms (therapy)
• Mice
• STAT3 Transcription Factor (administration & dosage, pharmacokinetics)
• Xenograft Model Antitumor Assays