P53-hdm2 interaction

Chene P, Fuchs J, Bohn J, Garcia-Echeverria C, Furet P, Fabbro D. A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines. J. Molec. Biol. 2000 299 245-253. 

Kritzer JA, et al. Helical beta-peptide inhibitors of the p53-hDM2 interaction. J. Am. Chem. Soc. 2004 126 9468-9469. 

Yin H, et al. Terphenyl-based helical mimetics that disrupt the 146. p53/HDM2 interaction. Angew Chem. Int. Ed. Engl. 2005 44 2704-2707. 

Kritzer JA, Zutshi R, Cheah M et al (2006) Miniature protein inhibitors of the p53-hDM2 interaction. Chembiochem 7 29-31... 

An Example The Design of Inhibitors of the p53-hdm2 Interaction 15.5.6.1 Biological Background... 

Table 15.5-2 Example of peptidic inhibitors used as tool compounds for studying the p53-hdm2 interaction. The IC50 values were obtained in a competition assay [49], The position of the three key residues Phel9, Trp23, and Leu26 is indicated...

Biological validation is a key step in any drug discovery programme because, even if a protein-protein interaction is a top drug target for medicinal chemistry, its inhibition should lead to the expected biological output. In the case of the p53-hdm2 interaction, the results obtained both in vitro and in vivo tend to demonstrate that inhibitors of this interaction will exert an anticancer activity in at least some tumors. 

For many years, the only synthetic low-molecular-weight inhibitors of the p53-hdm2 interaction described were not very potent. Only chalcone derivatives (6 - Fig. 15.5-5) [45], some polycyclic compounds (7 - Fig. 15.5-5) [56], and sulfonamides (8 - Fig. 15.5-5) [57] were described. A fungal metabolite, chlorofusin (9 - Fig. 15.5-5), was also described as an inhibitor of the p53-hdm2 interaction [58]. Finally, l,4-benzodiazepine-2-ones were proposed from a computational approach (10 - Fig. 15.5-5) [59]. 

These data were not very encouraging and, despite the attractiveness of this approach, it seemed that not only the druggability of the p53-hdm2 interaction... 

Fig. 15.5-5 Low-molecular-weight inhibitors of the p53-hdm2 interaction. 6 Chalcone derivative [45], 7 polycyclic compound [56], 8 sulfonamide [57], 9 chlorofusin, 10 1,4-benzodiazepine-2-one [59], 11 c/s-imidazoline [60].

P. Chene. J. Fuchs, I. Carena, P. Furet, C. Garcia Echeverria, Study of the cytotoxic effect of a peptidic inhibitor of the p53-hdm2 interaction in tumour cells, FEBS Lett. 2002, 529, 293-297. 

Nakahashi, A., Miura, N., Monde, K., and Tsukamoto, S. (2009) Stereochemical studies of hexylitaconic acid, an inhibitor of p53-HDM2 interaction. Bioorg. Med. Chem. Lett., 19, 3027-3030. 

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