EL133, Keap1 PINCH

EL133 is a highly cell-permeable Polymerization-Inducing Chimera (PINCH) rationally designed to exploit protein symmetry (homodimerism) as a selective vulnerability for functional protein knockout. Comprising two bardoxolone (BDX) moieties conjugated via a precise short polyethylene glycol (PEG2) linker, EL-133 acts as a covalent molecular bridge targeting Cysteine 151 (C151) within the Keap1 BTB domain to induce supramolecular assembly. This mechanism drives the rapid (>90%) and high-specificity precipitation of Keap1 from the soluble cytosolic fraction (insolubility EC50 = 102 nM in OCI-AML2; effective >500 nM), with global proteomics confirming COL1A1 as the sole significant off-target. By locking Keap1 in an inactive polymeric state, EL133 triggers robust, proteasome-independent activation of the Nrf2 pathway and Antioxidant Response Element (ARE) genes, resulting in distinct, sustained upregulation of NAD(P)H quinone dehydrogenase 1 (NQO1). Distinct from PROTACs or simple inhibitors, EL-133 functions as an autonomous sequestrator independent of cellular degradation machinery (lysosome/proteasome) or E3 ligase co-expression, effectively circumventing resistance mechanisms associated with effector dependency.