Through structure-activity relationship (SAR), in silico molecular docking studies, and cryo-EM studies, we identified hotspots on opposing ends of the SN-401 molecule that interact with separate regions of the SWELL1-LRRC8 complex: the carboxylate group with R103 in multiple LRRC8 subunits at a constriction in the pore, and the cyclopentyl group within the hydrophobic cleft formed by adjacent LRRC8 monomers; functioning like a molecular staple or tether to bind loosely associated SWELL1-LRRC8 monomers (especially in the setting of T2D) into a more stable hexameric structure. The gene discussed is LRRC8A; the disease is type 2 diabetes mellitus.