title: Small molecule STAT5-SH2 domain inhibitors exhibit potent antileukemia activity.
abstract: A growing body of evidence shows that Signal Transducer and Activator of Transcription 5 (STAT5) protein, a key member of the STAT family of signaling proteins, plays a pivotal role in the progression of many human cancers, including acute myeloid leukemia and prostate cancer. Unlike STAT3, where significant medicinal effort has been expended to identify potent direct inhibitors, Stat5 has been poorly investigated as a molecular therapeutic target. Thus, in an effort to identify direct inhibitors of STAT5 protein, we conducted an in vitro screen of a focused library of SH2 domain binding salicylic acid-containing inhibitors (∼150) against STAT5, as well as against STAT3 and STAT1 proteins for SH2 domain selectivity. We herein report the identification of several potent (K(i) < 5 μM) and STAT5 selective (>3-fold specificity for STAT5 cf. STAT1 and STAT3) inhibitors, BP-1-107, BP-1-108, SF-1-087, and SF-1-088. Lead agents, evaluated in K562 and MV-4-11 human leukemia cells, showed potent induction of apoptosis (IC(50)'s ∼ 20 μM) which correlated with potent and selective suppression of STAT5 phosphorylation, as well as inhibition of STAT5 target genes cyclin D1, cyclin D2, C-MYC, and MCL-1. Moreover, lead agent BP-1-108 showed negligible cytotoxic effects in normal bone marrow cells not expressing activated STAT5 protein. Inhibitors identified in this study represent some of the most potent direct small molecule, nonphosphorylated inhibitors of STAT5 to date.
authors.affiliation: Department of Chemistry, University of Toronto, 3359 Mississauga Road North, Mississauga, ON, L5L 1C6, Canada.
authors.forename: Brent D G
authors.initials: BD
authors.lastname: Page
authors.forename: Haytham
authors.initials: H
authors.lastname: Khoury
authors.forename: Rob C
authors.initials: RC
authors.lastname: Laister
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.forename: Megan
authors.initials: M
authors.lastname: Vellozo
authors.forename: Alessia
authors.initials: A
authors.lastname: Manzoli
authors.forename: Peibin
authors.initials: P
authors.lastname: Yue
authors.forename: James
authors.initials: J
authors.lastname: Turkson
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Gunning
mesh_terms: D000636:Aminosalicylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008958:Models, Molecular; D010766:Phosphorylation; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018909:src Homology Domains
chemical_list: C571525:4-(N-(4-cyclohexylbenzyl)-2-(N,2,4,6-tetramethylphenylsulfonamido)acetamido)-2-hydroxybenzoic acid; D000636:Aminosalicylic Acids; D000970:Antineoplastic Agents; D020033:Protein Isoforms; D050799:STAT5 Transcription Factor; D013449:Sulfonamides