Xie Fuchun, Li Bingbing X, Xiao Xiangshu
Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Program in Chemical Biology, Department of Physiology and Pharmacology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA; Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA; Knight Cardiovascular Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, USA.
Bioorg Med Chem Lett. 2017 Feb 15;27(4):994-998. doi: 10.1016/j.bmcl.2016.12.078. Epub 2016 Dec 31.
cAMP-response element binding protein (CREB) is a nuclear transcription factor that has been implicated in the pathogenesis and maintenance of various types of human cancers. Identification of small molecule inhibitors of CREB-mediated gene transcription has been pursued as a novel strategy for developing cancer therapeutics. We recently discovered a potent and cell-permeable CREB inhibitor called 666-15. 666-15 is a bisnaphthamide and has been shown to possess efficacious anti-breast cancer activity without toxicity in vivo. In this study, we designed and synthesized a series of analogs of 666-15 to probe the importance of regiochemistry in naphthalene ring B. Biological evaluations of these analogs demonstrated that the substitution pattern of the alkoxy and carboxamide in naphthalene ring B is very critical for maintaining potent CREB inhibition activity, suggesting that the unique bioactive conformation accessible in 666-15 is critically important.
环磷酸腺苷反应元件结合蛋白（CREB）是一种核转录因子，与多种人类癌症的发病机制和维持有关。鉴定CREB介导的基因转录的小分子抑制剂已被作为开发癌症治疗药物的一种新策略。我们最近发现了一种名为666-15的强效且可穿透细胞的CREB抑制剂。666-15是一种双萘酰胺，已被证明在体内具有有效的抗乳腺癌活性且无毒性。在本研究中，我们设计并合成了一系列666-15的类似物，以探究萘环B区域化学的重要性。这些类似物的生物学评估表明，萘环B中烷氧基和羧酰胺的取代模式对于维持强效的CREB抑制活性至关重要，这表明666-15中可获得的独特生物活性构象至关重要。
