Structure-Based Design of Spiro-oxindoles as Potent, Specific Small-Molecule Inhibitors of the MDM2−p53 Interaction
Ke Ding(National Institutes of Health), Yipin Lu(National Cancer Institute), Zaneta Nikolovska‐Coleska(University of Michigan–Ann Arbor), Guoping Wang(University of Michigan–Ann Arbor), Su Qiu(National Institutes of Health), Sanjeev Shangary(University of Michigan–Ann Arbor), Wei Gao(National Institutes of Health), Dongguang Qin(University of Michigan–Ann Arbor), Jeanne A. Stuckey(National Cancer Institute), Krzysztof Krajewski(National Institutes of Health), Peter P. Roller(University of Michigan–Ann Arbor), Shaomeng Wang(National Institutes of Health)
Cited by 690Open Access
Abstract
Potent, specific, non-peptide small-molecule inhibitors of the MDM2-p53 interaction were successfully designed. The most potent inhibitor (MI-63) has a K(i) value of 3 nM binding to MDM2 and greater than 10,000-fold selectivity over Bcl-2/Bcl-xL proteins. MI-63 is highly effective in activation of p53 function and in inhibition of cell growth in cancer cells with wild-type p53 status. MI-63 has excellent specificity over cancer cells with deleted p53 and shows a minimal toxicity to normal cells.
Related Papers
No related papers found
Powered by citation graph analysis