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

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 transcription3). 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 invitro, in tumor growth models, and in a leukemia mouse model, validating this new therapeutic target for resistant AML. Touching from a distance: Small molecules block STAT3 SH2 phosphotyrosine recognition by binding to the distal coiled-coil domain (CCD). Inhibition of this new CCD target site, which was identified by catalytic rhodium labeling, blocks tumor progression in a leukemia mouse model.