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Inside Cover: Disarming an Electrophilic Warhead: Retaining Potency in Tyrosine Kinase Inhibitor (TKI)‐Resistant CML Lines While Circumventing Pharmacokinetic Liabilities (ChemMedChem 8/2016)
Author(s) -
Ali Ahmed M.,
GómezBiagi Rodolfo F.,
Rosa David A.,
Lai PingShan,
Heaton William L.,
Park Ji Sung,
Eiring Anna M.,
Vellore Nadeem A.,
de Araujo Elvin D.,
Ball Dan P.,
Shouksmith Andrew E.,
Patel Ami B.,
Deininger Michael W.,
O'Hare Thomas,
Gunning Patrick T.
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Reports
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600185
Subject(s) - imatinib , tyrosine kinase , myeloid leukemia , tyrosine kinase inhibitor , pharmacology , chemistry , dasatinib , imatinib mesylate , cancer research , medicine , signal transduction , biochemistry , cancer
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 (t 1/2 =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).