复制蛋白A的蛋白质-蛋白质相互作用抑制剂的发现
Discovery of Protein-Protein Interaction Inhibitors of Replication Protein A.
作者信息
Patrone James D, Kennedy J Phillip, Frank Andreas O, Feldkamp Michael D, Vangamudi Bhavatarini, Pelz Nicholas F, Rossanese Olivia W, Waterson Alex G, Chazin Walter J, Fesik Stephen W
机构信息
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232 (USA).
出版信息
ACS Med Chem Lett. 2013 Jul 11;4(7):601-605. doi: 10.1021/ml400032y.
Abstract
Replication Protein A (RPA) is a ssDNA binding protein that is essential for DNA replication and repair. The initiation of the DNA damage response by RPA is mediated by protein-protein interactions involving the N-terminal domain of the 70 kDa subunit with partner proteins. Inhibition of these interactions increases sensitivity towards DNA damage and replication stress and may therefore be a potential strategy for cancer drug discovery. Towards this end, we have discovered two lead series of compounds, derived from hits obtained from a fragment-based screen, that bind to RPA70N with low micromolar affinity and inhibit the binding of an ATRIP-derived peptide to RPA. These compounds may offer a promising starting point for the discovery of clinically useful RPA inhibitors.
摘要
复制蛋白A（RPA）是一种单链DNA结合蛋白，对DNA复制和修复至关重要。RPA引发的DNA损伤反应是由涉及70 kDa亚基N端结构域与伴侣蛋白的蛋白质-蛋白质相互作用介导的。抑制这些相互作用会增加对DNA损伤和复制应激的敏感性，因此可能是癌症药物发现的潜在策略。为此，我们发现了两个先导化合物系列，它们源自基于片段筛选获得的活性分子，以低微摩尔亲和力与RPA70N结合，并抑制ATRIP衍生肽与RPA的结合。这些化合物可能为发现临床上有用的RPA抑制剂提供一个有前景的起点。
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3
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