BT503

BT503 is a novel, urea-based small molecule agonist of Krüppel-like factor 15 (KLF15) and a direct inhibitor of inhibitor of nuclear factor kappa-B kinase subunit beta (IKKβ). Developed by researchers at Stony Brook University, Long Island University, and collaborating institutions, BT503 was identified through a human podocyte-based high-throughput screen. It directly binds to the ATP-binding pocket of IKKβ (IC50 of 163 nM), preventing the phosphorylation of IκBα and subsequent nuclear translocation of NF-κB dimers (p50/p65). This inhibition of canonical NF-κB signaling restores KLF15 expression under cell stress, which is essential for maintaining podocyte differentiation and stabilizing the actin cytoskeleton. In preclinical models of proteinuric kidney disease (including LPS-induced, nephrotoxic serum nephritis, and HIV-1 transgenic mice), BT503 treatment significantly reduced proteinuria, podocyte effacement, and kidney injury, demonstrating potential therapeutic utility for podocytopathies such as focal segmental glomerulosclerosis (FSGS).