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: To improve the bioavailability of D-peptides in vivo, while retaining high cellular activity and specificity toward the GADD45β/MKK7 complex, we used a chemical optimization strategy based on structure-activity relationship and pharmacophore analyses (Figures S5A–S5C and Table S4). By combining these methods, we developed DTP3, a D-tripeptide with a molecular weight of 525 Da (Figure 5A), which retained all the main characteristics of the parental D-tetrapeptides in terms of bioactivity and specificity, including subnanomolar activity and high stability in vitro and potent and selective capacity to kill MM cells via apoptosis (Figures S5D–S5H), while exhibiting a superior pharmacokinetic profile compared with the parent molecules (discussed below).
Affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.