title: Disarming an Electrophilic Warhead: Retaining Potency in Tyrosine Kinase Inhibitor (TKI)-Resistant CML Lines While Circumventing Pharmacokinetic Liabilities.
abstract: 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 (SN 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 (Ki =15 μm), as well as selectivity over STAT1 (Ki >250 μm). 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 (t1/2 =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.
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, ON, L5L 1C6, Canada.|Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut, 71515, Egypt.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Ali
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, ON, L5L 1C6, Canada.
authors.forename: Rodolfo F
authors.initials: RF
authors.lastname: Gómez-Biagi
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, ON, L5L 1C6, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Rosa
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, ON, L5L 1C6, Canada.
authors.forename: Ping-Shan
authors.initials: PS
authors.lastname: Lai
authors.affiliation: Huntsman Cancer Institute, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, 84112, USA. michael.deininger@hci.utah.edu.
authors.forename: William L
authors.initials: WL
authors.lastname: Heaton
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, ON, L5L 1C6, Canada.
authors.forename: Ji Sung
authors.initials: JS
authors.lastname: Park
authors.affiliation: Huntsman Cancer Institute, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Eiring
authors.affiliation: Huntsman Cancer Institute, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Vellore
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, ON, L5L 1C6, Canada.
authors.forename: Elvin D
authors.initials: ED
authors.lastname: de Araujo
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, ON, L5L 1C6, Canada.
authors.forename: Dan P
authors.initials: DP
authors.lastname: Ball
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, ON, L5L 1C6, Canada.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Shouksmith
authors.affiliation: Huntsman Cancer Institute, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Ami B
authors.initials: AB
authors.lastname: Patel
authors.affiliation: Huntsman Cancer Institute, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Deininger
authors.affiliation: Huntsman Cancer Institute, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.affiliation: Department of Chemistry, University of Toronto Mississauga, Mississauga, ON, L5L 1C6, Canada. patrick.gunning@utoronto.ca.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D062366:para-Aminobenzoates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C000612981:SH-4-054; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D062366:para-Aminobenzoates
keywords: STAT3; chronic myeloid leukemia; covalent modification; imatinib resistance; protein-protein interactions