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. 2009 Dec 24;52(24):7970-3.
doi: 10.1021/jm901400z.

Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction

Shanghai Yu  1 , Dongguang Qin, Sanjeev Shangary, Jianyong Chen, Guoping Wang, Ke Ding, Donna McEachern, Su Qiu, Zaneta Nikolovska-Coleska, Rebecca Miller, Sanmao Kang, Dajun Yang, Shaomeng Wang
Affiliations

Potent and orally active small-molecule inhibitors of the MDM2-p53 interaction

Shanghai Yu et al. J Med Chem. .

Abstract

We report herein the design of potent and orally active small-molecule inhibitors of the MDM2-p53 interaction. Compound 5 binds to MDM2 with a K(i) of 0.6 nM, activates p53 at concentrations as low as 40 nM, and potently and selectively inhibits cell growth in tumor cells with wild-type p53 over tumor cells with mutated/deleted p53. Compound 5 has a good oral bioavailability and effectively inhibits tumor growth in the SJSA-1 xenograft model.

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Figures

Figure 1
Figure 1
Chemical structures of potent MDM2 inhibitors.
Figure 2
Figure 2
Dose-dependent p53 activation induced by compound 5 in SJSA-1 and HCT-116 cell lines, and its specificity in HCT-116 isogenic p53 knock-out cell line.
Figure 3
Figure 3
Western blot analysis of p53 activation induced by compounds 5 and 7. MI-61 was used as an inactive control, whereas racemic Nutlin-3 was used as a positive control.
Figure 4
Figure 4
Induction of cell death by 5 and 7 in the SJSA-1 cancer cell line with wild-type p53 status and in the SaOS-2 cancer cell line with deleted p53.
Figure 5
Figure 5
Antitumor activity of 5 alone and in combination with Irinotecan in the SJSA-1 xenograft model. (A). Tumor volume ; (B). Animal weight.
See this image and copyright information in PMC

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