Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein-Protein Interaction: Structure-Activity Studies Leading to Improved Potency
Isoindolinone Inhibitors of the Murine Double Minute 2 (MDM2)-p53 Protein-Protein Interaction: Structure-Activity Studies Leading to Improved Potency
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DOI：
10.1021/jm1011929
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发表时间：
2011-03-10
影响因子：
7.3
通讯作者：
Lunec, John
中科院分区：
文献类型：
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作者：
Hardcastle, Ian R.;Liu, Junfeng;Lunec, John
抑制MDM2-P53的相互作用已被证明产生了抗肿瘤作用，特别是在MDM2扩增的肿瘤中。异吲哚-酮支架已被证明是发现MDM2-P53拮抗剂的通用支架。先前报道的抑制剂，例如NU8231(7)和NU8165(49)的优化是由MDM2核磁共振滴定指导的，这表明了结合作用的关键领域有待探索。2-N-苄基和3-烷氧基的变异导致3-(4-nitrobenzyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one(74)被鉴定为一种有效的mdm2-p53抑制物(IC(50)=0.23+/-0.01muM)。对74个对映体的拆分表明，有效的MDM2-P53活性主要存在于(+)R-对映体上(74a；IC(50)=0.17+/-0.02µM)。关键化合物的细胞活性已经在具有明确的P53和MDM2状态的细胞系中进行了检测。化合物74a在MDM2扩增细胞中激活p53、MDM2和p21转录，并在生长抑制实验中对野生型p53细胞株显示出中等的选择性。
Inhibition of the MDM2-p53 interaction has been shown to produce an antitumor effect, especially in MDM2 amplified tumors.. The isoindolinone scaffold has proved to be versatile for the discovery of MDM2-p53 antagonists. Optimization of previously reported inhibitors, for example, NU8231 (7) and NU8165 (49), was guided by MDM2 NMR titrations, which indicated key areas of the binding interaction to be explored. Variation of the 2-N-benzyl and 3-alkoxy substituents resulted in the identification of 3-(4-nitrobenzyl)-3-((1-(hydroxymethyl)cyclopropyl)methoxy)-2-(4-nitrobenzyl)isoindolin-1-one (74) as a potent MDM2-p53 inhibitor (IC(50) = 0.23 +/- 0.01 mu M). Resolution of the enantiomers of 74 showed that potent MDM2-p53 activity primarily resided with the (+)R-enantiomer (74a; IC(50) = 0.17 +/- 0.02 mu M). The cellular activity of key compounds has been examined in cell lines with defined p53 and MDM2 status. Compound 74a activates p53, MDM2, and p21 transcription in MDM2 amplified cells and shows moderate selectivity for wild-type p53 cell lines in growth inhibition assays.