Chitsike Lennox, Yuan Chung-Hsiang, Roy Anuradha, Boyle Kristopher, Duerksen-Hughes Penelope J
Department of Basic Science, School of Medicine, Loma Linda University, Loma Linda, CA, USA.
High-Throughput Screening Laboratory, University of Kansas, Lawrence, KS, USA.
Oncotarget. 2021 Mar 16;12(6):549-561. doi: 10.18632/oncotarget.27908.
The incidence of human papillomavirus-positive head and neck squamous cell carcinoma (HPV-HNSCC) has increased dramatically over the past decades due to an increase in infection of the oral mucosa by HPV. The etiology of HPV-HNSCC is linked to expression of the HPV oncoprotein, E6, which influences tumor formation, growth and survival. E6 effects this oncogenic phenotype in part through inhibitory protein-protein interactions (PPIs) and accelerated degradation of proteins with tumor suppressor properties, such as p53 and caspase 8. Interfering with the binding between E6 and its cellular partners may therefore represent a reasonable pharmacological intervention in HPV tumors. In this study, we probed a small-molecule library using AlphaScreen™ technology to discover novel E6 inhibitors. Following a cascade of screens we identified and prioritized one hit compound. Structure activity relationship (SAR) studies of this lead uncovered an analog, 30-hydroxygambogic acid (GA-OH), that displayed improved activity. Further testing of this analog in a panel of HPV and HPV cell lines showed good potency and a large window of selectivity as demonstrated by apoptosis induction and significant inhibition of cell growth, cell survival in HPV cells. In summary, GA-OH may serve as a starting point for the development of potent E6-specific inhibitors.
在过去几十年中，由于人乳头瘤病毒（HPV）对口腔黏膜感染的增加，HPV阳性的头颈部鳞状细胞癌（HPV-HNSCC）的发病率急剧上升。HPV-HNSCC的病因与HPV致癌蛋白E6的表达有关，E6影响肿瘤的形成、生长和存活。E6部分通过抑制性蛋白质-蛋白质相互作用（PPI）以及加速具有肿瘤抑制特性的蛋白质（如p53和半胱天冬酶8）的降解来实现这种致癌表型。因此，干扰E6与其细胞伴侣之间的结合可能是对HPV肿瘤进行合理药物干预的一种方式。在本研究中，我们使用AlphaScreen™技术对一个小分子文库进行筛选，以发现新型E6抑制剂。经过一系列筛选，我们鉴定并确定了一个有活性的化合物。对该先导化合物的构效关系（SAR）研究发现了一种类似物，即30-羟基藤黄酸（GA-OH），其活性有所提高。在一组HPV和HPV细胞系中对该类似物进行的进一步测试显示出良好的效力和较大的选择性窗口，这通过凋亡诱导以及对HPV细胞中细胞生长和细胞存活的显著抑制得以证明。总之，GA-OH可能作为开发强效E6特异性抑制剂的起点。
