title: Potent and selective phosphopeptide mimetic prodrugs targeted to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3.
abstract: Signal transducer and activator of transcription 3 (Stat3), a target for anticancer drug design, is activated by recruitment to phosphotyrosine residues on growth factor and cytokine receptors via its SH2 domain. We report here structure-activity relationship studies on phosphopeptide mimics targeted to the SH2 domain of Stat3. Inclusion of a methyl group on the β-position of the pTyr mimic 4-phosphocinnamide enhanced affinity 2- to 3-fold. Bis-pivaloyloxymethyl prodrugs containing β-methylcinnamide, dipeptide scaffolds Haic and Nle-cis-3,4-methanoproline, and glutamine surrogates were highly potent, completely inhibiting phosphorylation of Stat3 Tyr705 at 0.5-1 μM in a variety of cancer cell lines. The inhibitors were selective for Stat3 over Stat1, Stat5, Src, and p85 of PI3K, indicating ability to discriminate individual SH2 domains in intact cells. At concentrations that completely inhibited Stat3 phosphorylation, the prodrugs were not cytotoxic to a panel of tumor cells, thereby showing clear distinction between cytotoxicity and effects downstream of activated Stat3.
authors.affiliation: Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, United States.
authors.forename: Pijus K
authors.initials: PK
authors.lastname: Mandal
authors.forename: Fengqin
authors.initials: F
authors.lastname: Gao
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lu
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ren
authors.forename: Rajagopal
authors.initials: R
authors.lastname: Ramesh
authors.forename: J Sanderson
authors.initials: JS
authors.lastname: Birtwistle
authors.forename: Kumaralal K
authors.initials: KK
authors.lastname: Kaluarachchi
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Chen
authors.forename: Robert C
authors.initials: RC
authors.lastname: Bast
authors.forename: Warren S
authors.initials: WS
authors.lastname: Liao
authors.forename: John S
authors.initials: JS
authors.lastname: McMurray
mesh_terms: D021581:Active Transport, Cell Nucleus; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011355:Prodrugs; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor / Q000737:chemistry*; D015398:Signal Transduction; D018909:src Homology Domains
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D019869:Phosphatidylinositol 3-Kinases