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Nuclear factor-κB (NF-κB) is a crucial transcription factor family involved in the regulation of immune and inflammatory responses and cell survival. The linear ubiquitin chain assembly complex (LUBAC), composed of the HOIL-1L, HOIP, and SHARPIN subunits, specifically generates Met1-linked linear ubiquitin chains through the ubiquitin ligase activity in HOIP, and activates the NF-κB pathway. We recently identified a chemical inhibitor of LUBAC, which we named HOIPIN-1 (HOIP inhibitor-1). To improve the potency of HOIPIN-1, we synthesized 7 derivatives (HOIPIN-2∼8), and analyzed their effects on LUBAC and NF-κB activation. Among them, HOIPIN-8 suppressed the linear ubiquitination activity by recombinant LUBAC at an IC₅₀ value of 11 nM, corresponding to a 255-fold increase over that of HOIPIN-1. Furthermore, as compared with HOIPIN-1, HOIPIN-8 showed 10-fold and 4-fold enhanced inhibitory …