Structure-based strategy for developing inhibitors of the kidney chloride channel CLC-Ka

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CLCs (the “Chloride Channel” family) are anion-selective transporters and channels ubiquitous in all organisms. Among them, CLC-Ka and CLC-Kb are essential for Cl– and water handling in the kidney. CLC-Ka is localized to the thin ascending limb, where it helps to establish the steep solute gradient in the inner medullary interstitium that drives renal water reabsorption. As such, CLC-Ka is a potential drug target for treating pathologic water retention (hyponatremia) that frequently complicates the management of patients with hypertension, heart failure, or cirrhosis. A specific CLC-Ka inhibitor would be invaluable for validating CLC-Ka as a drug target for manipulating renal water excretion. In this project, we leverage recent breakthroughs to develop selective CLC-Ka inhibitors. The first breakthrough is our discovery of BIM1, a substituted benzimidazole that displays >20-fold selectivity for CLC-Ka over its closest homolog CLC-Kb. The synthetic accessibility of BIM derivatives makes them well suited for further development. The second breakthrough is the revolution in cryo-electron microscopy, which enables high-resolution structure determination of challenging targets, including ion channels. A molecular structure of the BIM/CLC-K complex will identify which regions of the BIM molecule must be retained for potency/selectivity and which may be modified to improve pharmacokinetic properties. Guided by this information, we will use a medicinal chemistry approach to develop BIM derivatives with optimized potency, selectivity, and pharmacokinetic properties. Optimized BIM derivatives will be tested for in vivo efficacy.