Rhodium(II) Proximity‐Labeling Identifies a Novel Target Site on STAT3 for Inhibitors with Potent Anti‐Leukemia Activity

Abstract

AbstractNearly 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.