Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors.
Bottom Line: Here, we identify the interaction between the NF-κB-regulated antiapoptotic factor GADD45β 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 GADD45β/MKK7 complex, kills MM cells effectively, and, importantly, lacks toxicity to normal cells.Hence, cancer-selective targeting of the NF-κB pathway is possible and, at least for myeloma patients, promises a profound benefit.
Affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.Show MeSH
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Mentions: DTP3 showed high aqueous solubility and very high stability in human serum, owing to its resistance to proteolysis, with a good pharmacokinetic profile and excellent in vivo tolerability, suitable for a therapeutic purpose (Figure 7A; Figure S5D and Table S6).
Affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.