title: Conformationally constrained peptidomimetic inhibitors of signal transducer and activator of transcription. 3: Evaluation and molecular modeling.
abstract: Signal transducer and activator of transcription 3 (Stat3) is involved in aberrant growth and survival signals in malignant tumor cells and is a validated target for anticancer drug design. We are targeting its SH2 domain to prevent docking to cytokine and growth factor receptors and subsequent signaling. The amino acids of our lead phosphopeptide, Ac-pTyr-Leu-Pro-Gln-Thr-Val-NH(2), were replaced with conformationally constrained mimics. Structure-affinity studies led to the peptidomimetic, pCinn-Haic-Gln-NHBn (21), which had an IC(50) of 162 nM (fluorescence polarization), compared to 290 nM for the lead phosphopeptide (pCinn = 4-phosphoryloxycinnamate, Haic = (2S,5S)-5-amino-1,2,4,5,6,7-hexahydro-4-oxo-azepino[3,2,1-hi]indole-2-carboxylic acid). pCinn-Haic-Gln-OH was docked to the SH2 domain (AUTODOCK), and the two highest populated clusters were subjected to molecular dynamics simulations. Both converged to a common peptide conformation. The complex exhibits unique hydrogen bonding between Haic and Gln and Stat3 as well as hydrophobic interactions between the protein and pCinn and Haic.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
authors.forename: Pijus K
authors.initials: PK
authors.lastname: Mandal
authors.forename: Donald
authors.initials: D
authors.lastname: Limbrick
authors.forename: David R
authors.initials: DR
authors.lastname: Coleman
authors.forename: Garrett A
authors.initials: GA
authors.lastname: Dyer
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Ren
authors.forename: J Sanderson
authors.initials: JS
authors.lastname: Birtwistle
authors.forename: Chiyi
authors.initials: C
authors.lastname: Xiong
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Chen
authors.forename: James M
authors.initials: JM
authors.lastname: Briggs
authors.forename: John S
authors.initials: JS
authors.lastname: McMurray