Cancer-selective targeting of the NF-?B survival pathway with GADD45ß/MKK7 inhibitors

Constitutive NF ?B signaling promotes survival in multiple myeloma (MM) and other cancers; however current NF ?B targeting strategies lack cancer cell specificity. Here we identify the interaction between the NF ?B regulated antiapoptotic factor GADD45ß and the JNK kinase MKK7 as a therapeutic target in MM. Using a drug discovery strategy we developed DTP3 a D tripeptide which disrupts the GADD45ß/MKK7 complex kills MM cells effectively and importantly lacks toxicity to normal cells. DTP3 has similar anticancer potency to the clinical standard bortezomib but more than 100 fold higher cancer cell specificity in vitro. Notably DTP3 ablates myeloma xenografts in mice with no apparent side effects at the effective doses. Hence cancer selective targeting of the NF ?B pathway is possible and at least for myeloma patients promises a profound benefit.