Title

Disruption Of Transcriptionally Active Stat3 Dimers With Non-Phosphorylated, Salicylic Acid-Based Small Molecules: Potent In Vitro And Tumor Cell Activities

Keywords

Antitumor agents; Molecular recognition; Molecular therapeutics; Protein-protein interactions; Stat3

Abstract

In summary, we have developed a library of analogues of the previously reported Stat3 inhibitor S3I-201, the most potent member of which displays more than twice the original potency for Stat3 dimer disruption. Furthermore, the most active analogues SF-1-066 and SF-1-121 have shown impressive in vitro and whole-cell activities; this is possibly a result of the successful occupation of a third, hydrophobic subpocket of the Stat3 SH2 domain. In general, our studies demonstrate that appropriate scaffold extension into this subpocket, which is believed to be occupied by the R1 substituent, resulted in significant increases in potency, thereby validating our approach to enhancing the Stat3 inhibitory activity of S3I-201. Future synthetic studies are currently focused upon developing extended agents with optimized occupation of the R1 subpocket, as well as optimizing the sulfonamide portion of our inhibitors to enhance interactions in the tosylamide-binding subpocket. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.

Publication Date

8-17-2009

Publication Title

ChemBioChem

Volume

10

Issue

12

Number of Pages

1959-1964

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1002/cbic.200900172

Socpus ID

70349558529 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/70349558529

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