TY - JOUR
T1 - Conformationally constrained peptidomimetic inhibitors of Signal transducer and activator of transcription 3
T2 - Evaluation and molecular modeling
AU - Mandal, Pijus K.
AU - Limbrick, Donald
AU - Coleman IV, David R.
AU - Dyer, Garrett A.
AU - Ren, Zhiyong
AU - Birtwistle, J. Sanderson
AU - Xiong, Chiyi
AU - Chen, Xiaomin
AU - Briggs, James M.
AU - McMurray, John S
PY - 2009/4/23
Y1 - 2009/4/23
N2 - 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 IC50 of 162 nM (fluorescence polarization), compared to 290 nM for the lead phosphopeptide (pCinn = 4-phosphoryloxycinnamate, Haic = (2S,5S)-5-amino-l,2,4,5,6,7-hexahydro-4-oxo-azepino[3,2,l-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.
AB - 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 IC50 of 162 nM (fluorescence polarization), compared to 290 nM for the lead phosphopeptide (pCinn = 4-phosphoryloxycinnamate, Haic = (2S,5S)-5-amino-l,2,4,5,6,7-hexahydro-4-oxo-azepino[3,2,l-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.
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U2 - 10.1021/jm801491w
DO - 10.1021/jm801491w
M3 - Article
C2 - 19334714
AN - SCOPUS:65249166871
SN - 0022-2623
VL - 52
SP - 2429
EP - 2442
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 8
ER -