Novel anti-cancer compounds: structure-based discovery of chemical chaperons for p53.
Thermal stability of p53 is crucial in preventing cancer proliferation. Critical mutations which significantly destabilize p53 conformation prevent normal interaction between p53 and DNA and consequently interfere with its inhibitory function against cancer proliferation. The purpose of this study was to discover the small compounds called 'chemical chaperons' that can efficiently stabilize the functional p53 conformation and restore the anti-cancer activity. To search for such compounds, we performed a docking simulation using the AutoDock program and the ZINC database. Simply based on the docking energy, we extracted 70 compounds (GJC1-GJC70) and examined their anti-cancer activity using the MTT assay of the human colon cancer cells, HCT116. We found that two compounds, GJC29 and GJC30, significantly inhibited the proliferation of cancer cells compared to the positive control staurosporine. Interaction between p53 and novel anti-cancer compounds were confirmed using SPR measurements. Intriguingly, in the simulated binding mode, both compounds bind to the pocket in the vicinity of the residue V143, one of the mutation hot-spots in p53. Finally, we injected each compound subcutaneously into the nude mice implanted with HCT116 and found that GJC29 has a strong suppressive effect against cancer proliferation in vivo. In conclusion, p53 is an appropriate target for the rational design of the chemical chaperon for cancer treatment.
Okuda
Yumiko
Y
Division of Prion Research, Center for Emerging Infectious Diseases, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan.
Nakamura
Hironori K
HK
Kuwata
Kazuo
K
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016208:Databases, Factual; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D018832:Molecular Chaperones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018832:Molecular Chaperones; D016159:Tumor Suppressor Protein p53