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: Given the essential antiapoptotic role of GADD45β in MM and our previous results showing that GADD45β suppresses JNK signaling and apoptosis by blocking MKK7 via direct physical interaction (De Smaele et al., 2001; Papa et al., 2004, 2007), we aimed to develop selective inhibitors of this protein-protein interaction in order to induce cytotoxic JNK signaling in MM cells. We screened a simplified combinatorial library of 20,736 L-tetrapeptides to select compounds capable of disrupting the GADD45β/MKK7 complex (Figure S3A and Table S1). Iterative deconvolution of this library in ELISA competition assays, followed by secondary screening and optimization of the resulting hits, yielded two acetylated L-tetrapeptides of similar structure, namely, Ac-LTP1 and Ac-LTP2, which disrupted the GADD45β/MKK7 complex, in vitro, with remarkable half-maximal inhibitory concentration (IC50) values in the subnanomolar range (Figure 3A; Figure S3B and Table S2), in line with the top-end potencies of other hits isolated from similar peptide library screens (Houghten et al., 1999).
Affiliation: Department of Medicine, Centre for Cell Signalling and Inflammation, Imperial College London, London W12 0NN, UK.