zliming2004

罗氏抗癌新药Idasanutlin(RG7388)

罗氏抗癌新药Idasanutlin(RG7388)的化学结构 Chemical Structure of Roche’s Anticancer Agent Idasanutlin(RG-7388)

  2015年7月7日 Oncology 肿瘤

RG7388 (Idasanutlin) is the second generation inhibitor of p53-MDM2 interaction.It is orally active, potently and selectively antagonizing the p53-MDM2 interaction with Ki at low nM. Highly optimized from pyrrolidin-based derivatives, RG7388 represents a distinctive, brand-new structural category of MDM2 ligand, a significant departure from the nutlin-based, first generation ligands exemplified by RG7112. Like RG7112, RG7388 binds selectively to the p53 site on the surface of the MDM2 molecule, effectively displacing p53 from MDM2, leading to p53 stabilization and activation of the p53 pathway. However, RG7388, as compared with its predecessor, binds to the MDM2 protein with a higher potency and selectivity, and has substantially improved pharmacological properties and superior clinical efficacy at lower doses and exposures.

Chemical Structure of Idasanutlin_RG-7388_Antineoplastic_Roche

Generic Name:Idasanutlin
Synonym:RG-7388, RG7388, RO5503781
CAS Number:1229705-06-9
Chemical Name:4-[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carboxamido]-3-methoxybenzoic acid
Mechanism of Action:p53-MDM2 Inhibitor
Indication:Prostate cancer,Acute myeloid leukaemia, Essential thrombocythaemia; Polycythaemia vera
Originator:Roche
Developer:Roche,NHS Greater Glasgow and Clyde; University of Glasgow

来源:

1.Oren M. Decision making by p53: life, death and cancer. Cell Death Differ. 2003;10:431-442. PMID: 12719720
2.Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops. Oncogene. 2005;24:2899-2908. PMID: 15838523
3.Vassilev LT. MDM2 inhibitors for cancer therapy. Trends Mol Med. 2007;13:23-31. PMID: 17126603
4.Melnikova VO, Ananthaswamy HN. Chapter 8: P53 protein and non-melanoma skin cancer. In: Reichrath J, ed. Molecular Mechanisms of Basal Cell and Squamous Cell Carcinomas. Georgetown, TX: Landes Bioscience/Eurekah.com; 2006:66-72.
5.Vu BT, Vassilev L. Small-molecule inhibitors of the p53-MDM2 interaction. Curr Top Microbiol Immunol. 2011;348:151-172. PMID: 21046355
6.Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res. 1998;26:3453-3459. PMID: 9671804
7.Tan BX, Khoo KH, Lim TM, Lane DP. High Mdm4 levels suppress p53 activity and enhance its half-life in acute myeloid leukaemia. Oncotarget. 2014;5:933-943. PMID: 24659749
8.Ding Q, Zhang Z, Liu JJ, et al. Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development. J Med Chem. 2013;56:5979-5983. PMID: 23808545

This compound and its uses are investigational and have not been approved by the US Food and Drug Administration. Efficacy and safety have not been established. The information presented should not be construed as a recommendation for use. The relevance of findings in preclinical studies to humans is currently being evaluated.

评论