Edited by James E. Darnell, The Rockefeller University, New York, NY, and approved April 13, 2012 (received for review January 4, 2012)
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 (KD) 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.
↵1X.Z. and P.Y. contributed equally to this work.
Author contributions: X.Z., P.Y., B.D.G.P., A.T.N., J.Z., Y.C., P.T.G., and J.T. designed research; X.Z., P.Y., B.D.G.P., T.L., W.Z., A.T.N., and D.P. performed research; J.Z., Y.C., P.T.G., and J.T. contributed new reagents/analytic tools; X.Z., P.Y., B.D.G.P., W.Z., A.T.N., J.Z., Y.C., P.T.G., and J.T. analyzed data; and X.Z., P.Y., A.T.N., Y.C., P.T.G., and J.T. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
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