title: 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.affiliation: Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL 32827, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
authors.forename: Peibin
authors.initials: P
authors.lastname: Yue
authors.forename: Brent D G
authors.initials: BD
authors.lastname: Page
authors.forename: Tianshu
authors.initials: T
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Namanja
authors.forename: David
authors.initials: D
authors.lastname: Paladino
authors.forename: Jihe
authors.initials: J
authors.lastname: Zhao
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
authors.forename: James
authors.initials: J
authors.lastname: Turkson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001943:Breast Neoplasms / Q000628:therapy*; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000628:therapy*; D051379:Mice; D050796:STAT3 Transcription Factor / Q000008:administration & dosage / Q000493:pharmacokinetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human