Identification and characterization of small molecule inhibitors of the calcium-dependent S100B-p53 tumor suppressor interaction

被引:73
作者
Markowitz, J
Chen, J
Gitti, R
Baldisseri, DM
Pan, YP
Udan, R
Carrier, F
MacKerell, AD [1 ]
Weber, DJ
机构
[1] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA
[3] Univ Maryland, Sch Med, MD PhD Program, Baltimore, MD 21201 USA
关键词
D O I
10.1021/jm0497038
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The binding of S100B to p53 down-regulates wild-type p53 tumor suppressor activity in cancer cells such as malignant melanoma, so a search for small molecules that bind S100B and prevent S100B-p53 complex formation was undertaken. Chemical databases were computationally searched for potential inhibitors of S100B, and 60 compounds were selected for testing on the basis of energy scoring, commercial availability, and chemical similarity clustering. Seven of these compounds bound to S100B as determined by steady state fluorescence spectroscopy (1.0 muM less than or equal to K-D less than or equal to 120 muM) and five inhibited the growth of primary malignant melanoma cells (C8146A) at comparable concentrations (1.0 muM less than or equal to IC50 less than or equal to 50 muM). Additionally, saturation transfer difference (STD) NMR experiments confirmed binding and qualitatively identified protons from the small molecule at the small molecule-S100B interface. Heteronuclear single quantum coherence (HSQC) NMR titrations indicate that these compounds interact with the p53 binding site on S100B. An NMR-docked model of one such inhibitor, pentamidine, bound to Ca2+-loaded S100B was calculated using intermolecular NOE data between S100B and the drug, and indicates that pentamidine binds into the p53 binding site on S100B defined by helices 3 and 4 and loop 2 (termed the hinge region).
引用
收藏
页码:5085 / 5093
页数:9
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