Inside Cover: Disarming an Electrophilic Warhead: Retaining Potency in Tyrosine Kinase Inhibitor (TKI)-Resistant CML Lines While Circumventing Pharmacokinetic Liabilities (ChemMedChem 8/2016)
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- 作者：Prof. Ahmed M. Ali ; Dr. Rodolfo F. Gó ; mez-Biagi ; Dr. David A. Rosa ; Dr. Ping-Shan Lai ; William L. Heaton ; Ji Sung Park ; Dr. Anna M. Eiring ; Dr. Nadeem A. Vellore ; Dr. Elvin D. de Araujo ; Dan P. Ball ; Dr. Andrew E. Shouksmith ; Dr. Ami B. Patel ; Prof. Michael W. Deininger ; Dr. Thomas O' ; Hare and Prof. Patrick T. Gunning
- 关键词：chronic myeloid leukemia ; covalent modification ; imatinib resistance ; protein&ndash ; protein interactions ; STAT3
- 刊名：ChemMedChem
- 出版年：2016
- 出版时间：April 19, 2016
- 年：2016
- 卷：11
- 期：8
- 页码：731
- 全文大小：1086K
- ISSN：1860-7187
文摘
The inside cover picture shows the small molecule AM-1-124, an inhibitor of imatinib-resistant chronic myeloid leukemia (CML) cells. Pharmacologic blockade of the activation of signal transducer and activator of transcription 3 (STAT3) in tyrosine kinase inhibitor (TKI)-resistant CML cell lines characterized by kinase-independent resistance was shown to re-sensitize CML cells to TKI therapy, suggesting that STAT3 inhibitors in combination with TKIs are an effective combinatorial therapeutic for the treatment of CML. We have conducted a focused structure–activity relationship (SAR) study on SH-4-054, a promising in vitro anti-pSTAT3 inhibitor with limited bioavailability in vivo (t1/2=10 min), to afford AM-1-124, which had a lower molecular weight, a more selective cytotoxic effect against imatinib-resistant CML cells, and an improved half-life in CD-1 mice. More information can be found in the Full Paper by William L. Heaton, Michael W. Deininger, Patrick T. Gunning et al. on page 850 in Issue 8, 2016 (DOI: 10.1002/cmdc.201600021).