Abstract LB-354: A novel orally-bioavailable small-molecule inhibitor of Stat3 regresses human breast and lung cancer xenografts

Abstract

Abstract Constitutive activation of STAT3, a member of the Signal Transducer and Activator of Transcription (STAT) family of proteins, occurs with a high frequency in diverse human tumors and is a molecular abnormality promoting carcinogenesis and tumor progression. Although STAT3 has been targeted for anticancer drug development, there is presently no STAT3 drug in the clinic. To identify potent therapeutics for tumors harboring constitutively-active STAT3, the key dimerization step in STAT3 activation was targeted in small-molecule drug development. A novel, orally bio-available small-molecule inhibitor has been identified that binds STAT3 SH2 domain with a KD of 504 nM. BP-1-102 blocks constitutively-active STAT3 signaling and selectively inhibits growth, survival, migration and invasion of diverse STAT3-dependent tumor cells in vitro. BP-1-102-mediated inhibition of aberrantly-active STAT3 in tumor cells suppresses the expression of c-Myc, Cyclin D1, Bcl-xL, Survivin, and vascular endothelial growth factor (VEGF). Further, treatment with BP-1-102 of breast cancer cells harboring aberrantly-active STAT3 disrupts STAT3-NFκB cross-talk and blocks the phosphorylation of focal adhesion kinase and paxillin, while enhancing E-cadherin expression. Intravenous or oral administration of BP-1-102 furnishes micromolar or microgram levels in tumor tissues and inhibits growth of human breast and lung tumor xenografts. Data together identify BP-1-102 as a small-molecule STAT3 inhibitor with a great potential for clinical development. The oral bioavailability represents a substantial advancement in the discovery of small-molecule STAT3 inhibitors as novel anticancer drugs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-354. doi:1538-7445.AM2012-LB-354