Inhibiting Aberrant Signal Transducer and Activator of Transcription Protein Activation with Tetrapodal, Small Molecule Src Homology 2 Domain Binders: Promising Agents against Multiple Myeloma

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• 作者：Brent D. G. Page ; Danielle C. Croucher ; Zhi Hua Li ; Sina Haftchenary ; Victor H. Jimenez-Zepeda ; Jennifer Atkinson ; Paul A. Spagnuolo ; Yoong Lim Wong ; Robert Colaguori ; Andrew M. Lewis ; Aaron D. Schimmer ; Suzanne Trudel ; Patrick T. Gunning
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 26, 2013
• 年：2013
• 卷：56
• 期：18
• 页码：7190-7200
• 全文大小：853K
• 年卷期：v.56,no.18(September 26, 2013)
• ISSN：1520-4804

文摘

The signal transducer and activator of transcription (STAT) proteins represent a family of cytoplasmic transcription factors that regulate a pleiotropic range of biological processes. In particular, Stat3 protein has attracted attention as it regulates the expression of genes involved in a variety of malignant processes, including proliferation, survival, migration, and drug resistance. Multiple myeloma (MM) is an incurable hematologic malignancy that often exhibits abnormally high levels of Stat3 activity. Although current treatment strategies can improve the clinical management of MM, it remains uniformly incurable with a dismal median survival time post-treatment of 3鈥? years. Thus, novel targeted therapeutics are critically needed to improve MM patient outcomes. We herein report the development of a series of small molecule Stat3 inhibitors with potent anti-MM activity in vitro. These compounds showed high-affinity binding to Stat3鈥檚 SH2 domain, inhibited intracellular Stat3 phosphorylation, and induced apoptosis in MM cell lines at low micromolar concentrations.