title: Rhodium(II) Proximity-Labeling Identifies a Novel Target Site on STAT3 for Inhibitors with Potent Anti-Leukemia Activity.
abstract: Nearly 40 % of children with acute myeloid leukemia (AML) suffer relapse arising from chemoresistance, often involving upregulation of the oncoprotein STAT3 (signal transducer and activator of transcription 3). Herein, rhodium(II)-catalyzed, proximity-driven modification identifies the STAT3 coiled-coil domain (CCD) as a novel ligand-binding site, and we describe a new naphthalene sulfonamide inhibitor that targets the CCD, blocks STAT3 function, and halts its disease-promoting effects in vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML.
authors.affiliation: Department of Chemistry, Rice University, Houston, TX 77005 (USA).
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Minus
authors.affiliation: Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX 77030 (USA).
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Rice University, Houston, TX 77005 (USA).
authors.forename: Farrukh
authors.initials: F
authors.lastname: Vohidov
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX 77030 (USA).
authors.forename: Moses M
authors.initials: MM
authors.lastname: Kasembeli
authors.affiliation: Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX 77030 (USA).
authors.forename: Xin
authors.initials: X
authors.lastname: Long
authors.affiliation: Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX 77030 (USA).
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Krueger
authors.affiliation: Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX 77030 (USA).
authors.forename: Alexandra
authors.initials: A
authors.lastname: Stevens
authors.affiliation: Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX 77030 (USA).
authors.forename: Mikhail I
authors.initials: MI
authors.lastname: Kolosov
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX 77030 (USA). DJTweardy@mdanderson.org.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tweardy
authors.affiliation: Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX 77030 (USA).
authors.forename: Edward Allan R
authors.initials: EA
authors.lastname: Sison
authors.affiliation: Baylor College of Medicine, Texas Children's Cancer Center, Houston, TX 77030 (USA). MLREDELL@txch.org.
authors.forename: Michele S
authors.initials: MS
authors.lastname: Redell
authors.affiliation: Department of Chemistry, Rice University, Houston, TX 77005 (USA). zb1@rice.edu.
authors.forename: Zachary T
authors.initials: ZT
authors.lastname: Ball
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D002384:Catalysis; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D012238:Rhodium / Q000737:chemistry*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D009281:Naphthalenes; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D013449:Sulfonamides; D012238:Rhodium
keywords: anti-tumor agents; leukemia; protein modifications; rhodium; stat3