Cancer-Selective Targeting of the NF-kappa B Survival Pathway with GADD45 beta/MKK7 Inhibitors

Constitutive NF-B-K signaling promotes survival in multiple myeloma (MM) and other cancers; however, current NF-B-K-targeting strategies lack cancer cell specificity. Here, we identify the interaction between the NF-B-K-regulated antiapoptotic factor GADD45 beta 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 GADD45 beta/ 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 rnyeloma xenografts in mice with no apparent side effects at the effective doses. Hence, cancer-selective targeting of the NF-KB pathway is possible and, at least for myeloma patients, promises a profound benefit.