Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 10, Pages 3549-3563Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm2000882
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Funding
- National Cancer Institute [CA096652]
- MDACC SPORE in Ovarian Cancer [P50 CA083639]
- CTT/TI-3D Chemistry and Molecularly-Targeted Therapeutic Development
- NCI Cancer Center [CA016672]
- UT SPORE in Lung Cancer [P50 CA070907]
- MDACC SPORE in Melanoma [P50 CA093459]
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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 beta-position of the pTyr mimic 4-phosphocinnamide enhanced affinity 2- to 3-fold. Bis-pivaloyloxymethyl prodrugs containing beta-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,mu M 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.
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