A series of p105-based NF-κB super repressors, designated p-105(sr), have been designed. The p105(sr), no longer generates p50 and undergoes signal-induced degradation, effectively inhibiting all NF-κB activities. Additionally, p105(sr) significantly enhances tumor necrosis factor alpha (TNF-α)-mediated killing of MT1/2 skin papilloma cells when p50 homodimer activity is elevated. p105(sr) is an effective NF-κB super repressor with a broader range than other currently available IkBα super repressors. The novel repressor can be used in cells where a noncanical NF-κB activity is dominant or multiple NF-κB activities are activated.