ABSTRACT
Recurrence and drug resistance are major challenges in the treatment of acute myeloid leukemia (AML) that spur efforts to identify new clinical targets and active agents. STAT3 has emerged as a potential target in resistant AML, but inhibiting STAT3 function has proven challenging. This paper describes synthetic studies and biological assays for a naphthalene sulfonamide inhibitor class of molecules that inhibit G-CSF-induced STAT3 phosphorylation in cellulo and induce apoptosis in AML cells. We describe two different approaches to inhibitor design: first, variation of substituents on the naphthalene sulfonamide core allows improvements in anti-STAT activity and creates a more thorough understanding of anti-STAT SAR. Second, a novel approach involving hybrid sulfonamide-rhodium(ii) conjugates tests our ability to use cooperative organic-inorganic binding for drug development, and to use SAR studies to inform metal conjugate design. Both approaches have produced compounds with improved binding potency. In vivo and in cellulo experiments further demonstrate that these approaches can also lead to improved activity in living cells, and that compound 3aa slows disease progression in a xenograft model of AML.
Subject(s)
Antineoplastic Agents/chemistry , Leukemia, Myeloid, Acute/drug therapy , Naphthalenes/chemistry , Protein Kinase Inhibitors/chemistry , STAT3 Transcription Factor/antagonists & inhibitors , Sulfonamides/chemistry , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Mice , Models, Molecular , Molecular Targeted Therapy , Neoplasms, Experimental , Oxidation-Reduction , Protein Binding , Protein Kinase Inhibitors/pharmacology , STAT3 Transcription Factor/genetics , Structure-Activity RelationshipABSTRACT
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 transcriptionâ 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 inâ vitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML.
