Discovery of highly potent p53-MDM2 antagonists and structural basis for anti-acute myeloid leukemia activities.
Discovery of highly potent p53-MDM2 antagonists and structural basis for anti-acute myeloid leukemia activities.
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DOI：
10.1021/cb400728e
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发表时间：
2014-03-21
影响因子：
4
通讯作者：
Domling, Alexander
中科院分区：
文献类型：
--
作者：
Huang, Yijun;Wolf, Siglinde;Beck, Barbara;Koehler, Lisa-Maria;Khoury, Kareem;Popowicz, Grzegorz M.;Goda, Sayed K.;Subklewe, Marion;Twarda, Aleksandra;Holak, Tad A.;Domling, Alexander
抑制p53-MDM 2相互作用是一种有前途的非遗传毒性癌症治疗的新方法。阻断p53-MDM 2相互作用的药物的潜在应用是急性髓性白血病（AML），因为在大多数患者中存在野生型p53（wt p53）。尽管在早期开发中有几种p53-MDM 2拮抗剂的非常有希望的临床前结果，但这些化合物中没有一种已经证明可用作下一代抗癌剂。在此，我们报告了YH 239-EE（游离羧酸化合物YH 239的乙酯）的设计、合成和优化，其是一种有效的p53-MDM 2拮抗剂和凋亡诱导剂，其特征在于许多白血病细胞系以及患者来源的AML原始细胞样品。MDM 2（p53受体）和YH 239之间相互作用的结构基础通过共晶体结构阐明。YH 239-EE作为前药，是诱导AML细胞和患者样本凋亡的最有效化合物。与参比化合物相比，观察到的上级活性为YH 239-EE的进一步研究和进展提供了临床前基础。
The inhibition of p53-MDM2 interaction is a promising new approach to non-genotoxic cancer treatment. A potential application for drugs blocking the p53-MDM2 interaction is acute myeloid leukemia (AML) due to the occurrence of wild type p53 (wt p53) in the majority of patients. Although there are very promising preclinical results of several p53-MDM2 antagonists in early development, none of the compounds have yet proven the utility as a next generation anticancer agent. Herein we report the design, synthesis and optimization of YH239-EE (ethyl ester of the free carboxylic acid compound YH239), a potent p53-MDM2 antagonizing and apoptosis-inducing agent characterized by a number of leukemia cell lines as well as patient-derived AML blast samples. The structural basis of the interaction between MDM2 (the p53 receptor) and YH239 is elucidated by a co-crystal structure. YH239-EE acts as a prodrug and is the most potent compound that induces apoptosis in AML cells and patient samples. The observed superior activity compared to reference compounds provides the preclinical basis for further investigation and progression of YH239-EE.
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