发现用于潜在临床开发的强效口服活性p53-MDM2抑制剂RO5353和RO2468。
Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development.
作者信息
Zhang Zhuming, Chu Xin-Jie, Liu Jin-Jun, Ding Qingjie, Zhang Jing, Bartkovitz David, Jiang Nan, Karnachi Prabha, So Sung-Sau, Tovar Christian, Filipovic Zoran M, Higgins Brian, Glenn Kelli, Packman Kathryn, Vassilev Lyubomir, Graves Bradford
机构信息
Discovery Chemistry, Discovery Technologies, Discovery Oncology, and Non-Clinical Development, Roche Pharma Research, Hoffmann-La Roche, Inc. , 340 Kingsland Street, Nutley, New Jersey 07110, United States.
出版信息
ACS Med Chem Lett. 2013 Dec 29;5(2):124-7. doi: 10.1021/ml400359z. eCollection 2014 Feb 13.
Abstract
The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives. Here we report two new potent, selective, and orally active p53-MDM2 antagonists, RO5353 and RO2468, as follow-ups with promising potential for clinical development.
摘要
开发小分子MDM2抑制剂以恢复功能失调的p53活性是一种新型癌症治疗方法。在之前的一篇通讯中，公开了导致鉴定出一种非咪唑啉MDM2抑制剂RG7388的研究工作，并揭示了这类基于吡咯烷的抑制剂所具有的理想体外和体内药理学特性。鉴于这类化合物的丰富性以及为确保临床成功而对多种化学结构的迫切需求，研究范围扩大到评估其他衍生物。在此，我们报告两种新的强效、选择性和口服活性的p53-MDM2拮抗剂RO5353和RO2468，作为具有临床开发潜力的后续研究成果。
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本文引用的文献
1
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J Med Chem. 2013 Jul 25;56(14):5979-83. doi: 10.1021/jm400487c. Epub 2013 Jul 16.
2
A potent small-molecule inhibitor of the MDM2-p53 interaction (MI-888) achieved complete and durable tumor regression in mice.一种强效的 MDM2-p53 相互作用小分子抑制剂（MI-888）在小鼠中实现了完全和持久的肿瘤消退。
J Med Chem. 2013 Jul 11;56(13):5553-61. doi: 10.1021/jm4005708. Epub 2013 Jun 20.
3
Diastereomeric spirooxindoles as highly potent and efficacious MDM2 inhibitors.具有高度效力和疗效的非对映体螺环氧化吲哚作为 MDM2 抑制剂。
J Am Chem Soc. 2013 May 15;135(19):7223-34. doi: 10.1021/ja3125417. Epub 2013 May 3.
4
Inhibitors of the p53/hdm2 protein-protein interaction-path to the clinic.p53/hdm2 蛋白-蛋白相互作用抑制剂-通往临床之路。
Bioorg Med Chem Lett. 2013 May 1;23(9):2480-5. doi: 10.1016/j.bmcl.2013.03.034. Epub 2013 Mar 16.
5
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Lancet Oncol. 2012 Nov;13(11):1133-40. doi: 10.1016/S1470-2045(12)70474-6. Epub 2012 Oct 17.
6
Awakening guardian angels: drugging the p53 pathway.唤醒守护天使：抑制 p53 通路。
Nat Rev Cancer. 2009 Dec;9(12):862-73. doi: 10.1038/nrc2763.
7
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8
MDM2 inhibitors for cancer therapy.用于癌症治疗的MDM2抑制剂。
Trends Mol Med. 2007 Jan;13(1):23-31. doi: 10.1016/j.molmed.2006.11.002. Epub 2006 Nov 28.
9
Structure-based design of spiro-oxindoles as potent, specific small-molecule inhibitors of the MDM2-p53 interaction.基于结构的螺环氧化吲哚类化合物设计，作为MDM2-p53相互作用的强效、特异性小分子抑制剂。
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10
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