Chalcone derivatives antagonize interactions between the human oncoprotein MDM2 and p53

被引:250
作者
Stoll, R
Renner, C
Hansen, S
Palme, S
Klein, C
Belling, A
Zeslawski, W
Kamionka, M
Rehm, T
Mühlhahn, P
Schumacher, R
Hesse, F
Kaluza, B
Voelter, W
Engh, RA
Holak, TA [1 ]
机构
[1] Max Planck Inst Biochem, D-82152 Martinsried, Germany
[2] Roche Diagnost GmbH, Pharmaceut Res, D-82372 Penzberg, Germany
[3] Univ Tubingen, Inst Physiol Chem, Dept Phys Biochem, D-72076 Tubingen, Germany
关键词
D O I
10.1021/bi000930v
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The oncoprotein MDM2 inhibits the tumor suppressor protein p53 by binding to the p53 transactivation domain. The p53 gene is inactivated in many human tumors either by mutations or by binding to oncogenic proteins. In some tumors, such as soft tissue sarcomas, overexpression of MDM2 inactivates an otherwise intact p53, disabling the genome integrity checkpoint and allowing cell cycle progression of defective cells. Disruption of the MDM2/p53 interaction leads to increased p53 levels and restored p53 transcriptional activity, indicating restoration of the genome integrity check and therapeutic potential for MDM2/p53 binding antagonists. Here, we show by multidimensional NMR spectroscopy that chalcones (1,3-diphenyl-2-propen-1-ones) are MDM2 inhibitors that bind to a subsite of the p53 binding cleft of human MDM2. Biochemical experiments showed that these compounds can disrupt the MDM2/p53 protein complex, releasing p53 from both the p53/MDM2 and DNA-bound p53/MDM2 complexes. These results thus offer a starting basis for structure-based drug design of cancer therapeutics.
引用
收藏
页码:336 / 344
页数:9
相关论文
共 40 条
  • [31] ONCOPROTEIN MDM2 CONCEALS THE ACTIVATION DOMAIN OF TUMOR SUPPRESSOR-P53
    OLINER, JD
    PIETENPOL, JA
    THIAGALINGAM, S
    GVURIS, J
    KINZLER, KW
    VOGELSTEIN, B
    [J]. NATURE, 1993, 362 (6423) : 857 - 860
  • [32] AMPLIFICATION OF A GENE ENCODING A P53-ASSOCIATED PROTEIN IN HUMAN SARCOMAS
    OLINER, JD
    KINZLER, KW
    MELTZER, PS
    GEORGE, DL
    VOGELSTEIN, B
    [J]. NATURE, 1992, 358 (6381) : 80 - 83
  • [33] Licochalcone A: An inducer of cell differentiation and cytotoxic agent from Pogostemon cablin
    Park, EJ
    Park, HR
    Lee, JS
    Kim, JW
    [J]. PLANTA MEDICA, 1998, 64 (05) : 464 - 466
  • [34] Pellecchia M, 1999, NAT STRUCT BIOL, V6, P336
  • [35] ANTI-TUMORIGENIC CHALCONES
    SHIBATA, S
    [J]. STEM CELLS, 1994, 12 (01) : 44 - 52
  • [36] Discovering high-affinity ligands for proteins: SAR by NMR
    Shuker, SB
    Hajduk, PJ
    Meadows, RP
    Fesik, SW
    [J]. SCIENCE, 1996, 274 (5292) : 1531 - 1534
  • [37] GRADIENT-TAILORED WATER SUPPRESSION FOR H-1-N-15 HSQC EXPERIMENTS OPTIMIZED TO RETAIN FULL SENSITIVITY
    SKLENAR, V
    PIOTTO, M
    LEPPIK, R
    SAUDEK, V
    [J]. JOURNAL OF MAGNETIC RESONANCE SERIES A, 1993, 102 (02) : 241 - 245
  • [38] p53 mediated death of cells overexpressing MDM2 by an inhibitor of MDM2 interaction with p53
    Wasylyk, C
    Salvi, R
    Argentini, M
    Dureuil, C
    Delumeau, I
    Abecassis, J
    Debussche, L
    Wasylyk, B
    [J]. ONCOGENE, 1999, 18 (11) : 1921 - 1934
  • [39] WATTENBERG L, 1995, J CELL BIOCHEM, P162
  • [40] Wuthrich K., 1986, NMR PROTEINS NUCL AC, DOI DOI 10.1051/EPN/19861701011