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Disarming an Electrophilic Warhead: Retaining Potency in Tyrosine Kinase Inhibitor (TKI)‐Resistant CML Lines While Circumventing Pharmacokinetic Liabilities
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 - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600021
Subject(s) - pharmacology , chemistry , tyrosine kinase , tyrosine kinase inhibitor , stat protein , in vivo , stat3 , kinome , myeloid leukemia , pharmacokinetics , kinase , cancer research , medicine , biochemistry , biology , signal transduction , cancer , microbiology and biotechnology
Pharmacologic blockade of the activation of signal transducer and activator of transcription 3 (STAT3) in tyrosine kinase inhibitor (TKI)‐resistant chronic myeloid leukemia (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. Benzoic acid‐ and hydroxamic acid‐based STAT3 inhibitors SH‐4‐054 and SH‐5‐007, developed previously in our laboratory, demonstrated promising activity against these resistant CML cell lines. However, pharmacokinetic studies in murine models (CD‐1 mice) revealed that both SH‐4‐054 and SH‐5‐007 are susceptible to glutathione conjugation at the para position of the pentafluorophenyl group via nucleophilic aromatic substitution (S N Ar). To determine whether the electrophilicity of the pentafluorophenyl sulfonamide could be tempered, an in‐depth structure–activity relationship (SAR) study of the SH‐4‐054 scaffold was conducted. These studies revealed that AM‐1‐124, possessing a 2,3,5,6‐tetrafluorophenylsulfonamide group, retained STAT3 protein affinity ( K i =15 μ m ), as well as selectivity over STAT1 ( K i >250 μ m ). Moreover, in both hepatocytes and in in vivo pharmacokinetic studies (CD‐1 mice), AM‐1‐124 was found to be dramatically more stable than SH‐4‐054 ( t 1/2 =1.42 h cf. 10 min, respectively). AM‐1‐124 is a promising STAT3‐targeting inhibitor with demonstrated bioavailability, suitable for evaluation in preclinical cancer models.