Benzodiazepinedione inhibitors of the Hdm2:p53 complex suppress human tumor cell proliferation in vitro and sensitize tumors to doxorubicin in vivo

被引:149
作者
Koblish, HK [1 ]
Zhao, SY [1 ]
Franks, CF [1 ]
Donatelli, RR [1 ]
Tominovich, RM [1 ]
LaFrance, LV [1 ]
Leonard, KA [1 ]
Gushue, JM [1 ]
Parks, DJ [1 ]
Calvo, RR [1 ]
Milkiewicz, KL [1 ]
Marugán, JJ [1 ]
Raboisson, P [1 ]
Cummings, MD [1 ]
Grasberger, BL [1 ]
Johnson, DL [1 ]
Lu, TB [1 ]
Molloy, CJ [1 ]
Maroney, AC [1 ]
机构
[1] Johnson & Johnson Pharmaceut Res & Dev LLC, Spring House, PA 19477 USA
关键词
D O I
10.1158/1535-7163.MCT-05-0199
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The activity and stability of the p53 tumor suppressor are regulated by the human homologue of the mouse double minute 2 (Hdm2) oncoprotein. It has been hypothesized that small molecules disrupting the Hdm2:p53 complex would allow for the activation of p53 and result in growth suppression. We have identified small-molecule inhibitors of the Hdm2:p53 interaction using our proprietary ThermoFluor microcalorimetry technology. Medicinal chemistry and structure-based drug design led to the development of an optimized series of benzodiazepinediones, including TDP521252 and TDP665759. Activities were dependent on the expression of wild-type (wt) p53 and Hdm2 as determined by lack of potency in mutant or null p53-expressing cell lines or cells engineered to no longer express Hdm2 and wt p53. TDP521252 and TDP665759 inhibited the proliferation of wt p53-expressing cell lines with average IC50S Of 14 and 0.7 mu mol/L, respectively. These results correlated with the direct cellular dissociation of Hdm2 from wt p53 observed within 15 minutes in JAR choriocarcinoma cells. Additional activities of these inhibitors in vitro include stabilization of p53 protein levels, up-regulation of p53 target genes in a DNA damage-independent manner, and induction of apoptosis in HepG2 cells. Administration of TDP665759 to mice led to an increase in p21(waf1/cip1) levels in liver samples. Finally, TDP665759 synergizes with doxorubicin both in culture and in an A375 xenograft model to decrease tumor growth. Taken together, these data support the potential utility of small-molecule inhibitors of the Hdm2:p53 interaction for the treatment of wt p53-expressing tumors.
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页码:160 / 169
页数:10
相关论文
共 66 条
  • [1] Bartel F, 2004, MOL CANCER RES, V2, P29
  • [2] Reversal of cisplatin resistance with a BH3 mimetic, (-)-gossypol, in head and neck cancer cells:: role of wild-type p53 and Bcl-XL
    Bauer, JA
    Trask, DK
    Kumar, B
    Los, G
    Castro, J
    Lee, JSJ
    Chen, JY
    Wang, SM
    Bradford, CR
    Carey, TE
    [J]. MOLECULAR CANCER THERAPEUTICS, 2005, 4 (07) : 1096 - 1104
  • [3] p53 gene mutation:: software and database
    Béroud, C
    Soussi, T
    [J]. NUCLEIC ACIDS RESEARCH, 1998, 26 (01) : 200 - 204
  • [4] BOTTERY M, 1997, ED MANAGEMENT ADM, V25, P7
  • [5] Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo
    Bottger, A
    Bottger, V
    Sparks, A
    Liu, WL
    Howard, SF
    Lane, DP
    [J]. CURRENT BIOLOGY, 1997, 7 (11) : 860 - 869
  • [6] A novel cellular protein (MTBP) binds to MDM2 and induces a G1 arrest that is suppressed by MDM2
    Boyd, MT
    Vlatkovic, N
    Haines, DS
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (41) : 31883 - 31890
  • [7] p53 alterations are predictive of chemoresistance and aggressiveness in ovarian carcinomas: A molecular and immunohistochemical study
    Buttitta, F
    Marchetti, A
    Gadducci, A
    Pellegrini, S
    Morganti, M
    Carnicelli, V
    Cosio, S
    Gagetti, O
    Genazzani, AR
    Bevilacqua, G
    [J]. BRITISH JOURNAL OF CANCER, 1997, 75 (02) : 230 - 235
  • [8] Synergistic activation of p53 by inhibition of MDM2 expression and DNA damage
    Chen, LH
    Agrawal, S
    Zhou, WQ
    Zhang, RW
    Chen, JD
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (01) : 195 - 200
  • [9] Ubiquitous induction of p53 in tumor cells by antisense inhibition of MDM2 expression
    Chen, LH
    Lu, WG
    Agrawal, SH
    Zhou, WQ
    Zhang, RW
    Chen, JD
    [J]. MOLECULAR MEDICINE, 1999, 5 (01) : 21 - 34
  • [10] Inhibiting the p53-MDM2 interaction:: An important target for cancer therapy
    Chène, P
    [J]. NATURE REVIEWS CANCER, 2003, 3 (02) : 102 - 109