Nuclear factor κB (NF-κB) is an important transcriptional regulator that is involved in numerous cellular processes, including cell proliferation, immune response, cell survival, and malignant transformation. It relies on the ubiquitin-proteasome system (UPS) for several of the steps in the concerted cascade of its activation. Previously, we showed that the ubiquitin (Ub) ligase KPC1 is involved in ubiquitination and limited proteasomal processing of the NF-κB1 p105 precursor to generate the p50 active subunit of the "canonical" heterodimeric transcription factor p50-p65. Overexpression of KPC1 with the generation of an excessive amount of p50 was shown to suppress tumors, an effect which is due to multiple mechanisms. Among them are suppression of expression of programmed cell death-ligand 1 (PD-L1), overexpression of a broad array of tumor suppressors, and secretion of cytokines which results in recruitment of suppressive immune cells into the tumor. Here, we show that the site of KPC1 to which p105 binds is exceptionally short and is made up of the seven amino acids WILVRLW. Attachment of this short stretch to a small residual part (∼20%) of the ligase that also contains the essential Really Interesting New Gene (RING)-finger domain was sufficient to bind p105, conjugate to it Ub, and suppress tumor growth in an animal model. Fusion of the seven amino acids to a Von Hippel-Lindau protein (pVHL)-binding ligand (which serves as a "universal" ligase for many proteolysis-targeting chimeras; PROTACs) resulted in a compound that stimulated conjugation of Ub to p105 in a cell-free system and its processing to p50 in cells and restricted cell growth.