PFI-1 (PF-6405761)

PFI-1(PF-6405761)是BET的选择性抑制剂,对BRD4和BRD2的IC50值分别为220 nM和98 nM[1]。

BET家族转录调节因子包括BRD2、BRD3、BRD4和BRDT,这些调节因子在细胞增殖、细胞周期中及细胞凋亡过程中发挥关键作用。研究表明BRD4与许多促进生长转录、抗凋亡基因的肿瘤的存活有关。众所周知，BET是表观遗传的指示器，它可以选择性地在组蛋白端结合乙酰化赖氨酸残基，近期在治疗NUT中线癌和几种血癌中，BET抑制剂显得较重要[2,3]。

PFI-1是一个有效的BET抑制剂，和已报导的BET抑制剂JQ1有相似的选择性。在BEAS-2Bs细胞实验中，PFI-1处理显著地抑制了由IL-1β/过氧化氢诱导的IL-6和CXCL8的释放[4]。在对BET抑制剂敏感的白血病细胞系MV4中，PFI-1处理通过作用于BRD4来诱导细胞周期和细胞凋亡[1]。在NET细胞系中做试验，浓度为100 nM – 1 μM的PFI-1抑制BET活性而降低细胞增殖[5]。

参考文献：
[1]. Picaud, S., et al., PFI-1, a highly selective protein interaction inhibitor, targeting BET Bromodomains. Cancer Res, 2013. 73(11): p. 3336-46.
[2]. Perry, M.M., et al., BET bromodomains regulate TGF-beta-induced proliferation and cytokine release in asthmatic airway smooth muscle. J Biol Chem, 2015.
[3]. Yu, L., et al., Small-Molecule BET Inhibitors in Clinical and Preclinical Development and Their Therapeutic Potential. Curr Top Med Chem, 2015.
[4]. Khan, Y.M., et al., Brd4 is essential for IL-1beta-induced inflammation in human airway epithelial cells. PLoS One, 2014. 9(4): p. e95051.
[5]. Kate E Lines, et al., Epigenetic modifiers reduce proliferation of human neuroendocrine tumour cell lines. Endocrine Abstracts, 2013. 31: p149.