title: An oxazole-based small-molecule Stat3 inhibitor modulates Stat3 stability and processing and induces antitumor cell effects.
abstract: Stat3 is hyperactivated in many human tumors and represents a valid target for anticancer drug design. We present a novel small-molecule Stat3 inhibitor, S3I-M2001, and describe the dynamics of intracellular processing of activated Stat3 within the context of the biochemical and biological effects of the Stat3 inhibitor. S3I-M2001 is an oxazole-based peptidomimetic of the Stat3 Src homology (SH) 2 domain-binding phosphotyrosine peptide that selectively disrupts active Stat3:Stat3 dimers. Consequently, hyperactivated Stat3, which hitherto occurs as "dotlike" structures of nuclear bodies, undergoes an early aggregation into nonfunctional perinuclear aggresomes and a late-phase proteasome-mediated degradation in malignant cells treated with S3I-M2001. Thus, S3I-M2001 inhibited Stat3-dependent transcriptional regulation of tumor survival genes, such as Bcl-xL. Furthermore, Stat3-dependent malignant transformation, survival, and migration and invasion of mouse and human cancer cells harboring persistently activated Stat3 were inhibited by S3I-M2001. Finally, S3I-M2001 inhibited growth of human breast tumor xenografts. The study identifies a novel Stat3 inhibitor, S3I-M2001, with antitumor cell effects mediated in part through a biphasic loss of functional Stat3. The study represents the first on intracellular Stat3 stability and processing following inhibition by a small molecule that has significant antitumor activity.
authors.affiliation: BioMolecular Science Center, Department of Molecular Biology and Microbiology, University of Central Florida College of Medicine, Orlando, Florida 32826, USA.
authors.forename: Khandaker A Z
authors.initials: KA
authors.lastname: Siddiquee
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
authors.forename: Matthew
authors.initials: M
authors.lastname: Glenn
authors.forename: William P
authors.initials: WP
authors.lastname: Katt
authors.forename: Shumin
authors.initials: S
authors.lastname: Zhang
authors.forename: Christopher
authors.initials: C
authors.lastname: Schrock
authors.forename: Christopher
authors.initials: C
authors.lastname: Schroeck
authors.forename: Said M
authors.initials: SM
authors.lastname: Sebti
authors.forename: Richard
authors.initials: R
authors.lastname: Jove
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hamilton
authors.forename: James
authors.initials: J
authors.lastname: Turkson
mesh_terms: D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010080:Oxazoles / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D010080:Oxazoles; D050796:STAT3 Transcription Factor