Discovery of novel estrogen-related receptor alpha inverse agonists by virtual screening and biological evaluation
Discovery of novel estrogen-related receptor alpha inverse agonists by virtual screening and biological evaluation
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通过虚拟筛选和生物学评价发现新型雌激素相关受体α反向激动剂
DOI：
10.1080/07391102.2018.1462736
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发表时间：
2019
影响因子：
4.4
通讯作者：
Yuan Haoliang
中科院分区：
文献类型：
--
作者：
Zhao Hui;Lin Chao;Hu Kaiwen;Wen Xiaoan;Yuan Haoliang
雌激素相关受体（ERR）是核受体（NR）超家族成员，包括ERRα、ERRβ和ERRγ。雌激素受体长期以来被归类为孤儿受体，因为它们不与内源性雌激素或任何已知的天然配体结合。然而，最新的研究表明胆固醇可能是其内源性配体（Wei et al.，2016年）。ERRα和ERRβ在1988年首次使用ER的DNA结合结构域（DBD）作为杂交探针来筛选重组DNA文库而被鉴定（Giguere，Yang，Segui，& Evans，1988），而ERRγ随后被报道（Eudy等人，1998年）。ERRα主要在代谢活性组织中表达，如肠、棕色脂肪组织和骨骼肌。ERRβ在早期发育中起着关键作用，但其表达在成年阶段受到高度限制，并且只能在成年眼睛、内耳、心脏和肾脏中以低水平检测到。ERRγ的确切功能尚不清楚，但它主要在脊髓和中枢神经系统中表达（Heard，Norby，霍洛威，& Vissing，2000）。遗传和功能分析表明，ERRα是线粒体生物发生的关键调节因子，在调节三羧酸（TCA）代谢、氧化磷酸化（OXPHOS）、与过氧化物酶体增殖物激活受体γ共激活因子（PGC-1）和核受体相互作用蛋白140（RIP-140）相互作用的糖酵解（Giguere，2008年）。ERRα的下游靶基因是PGC-1α（Liu & Lin，2011）、中链酰基辅酶A脱氢酶（MCAD）（Sladek，Bader，& Giguere，1997）、丙酮酸脱氢酶激酶4（PDK 4）（Wende，Huss，Schaeffer，Giguere，& Kelly，2005）和ERRα（维莱纳& Kralli，2008）。值得注意的是，经典的雌激素受体（ER）和雌激素受体之间的高度同源性为ER参与ER信号通路提供了结构基础。ERRα和ERα具有一些共同的靶基因（如pS2、乳铁蛋白和骨桥蛋白），在转录过程的多个步骤中具有功能性串扰。这意味着ERRα可能参与雌激素依赖性疾病，包括乳腺癌、卵巢癌和结肠癌。对于与雌激素相关但不依赖雌激素的肿瘤，如三阴性和基底细胞样乳腺癌（BLBC），传统的激素治疗无效。然而，ERRα在ER阴性乳腺癌中过表达，并且它可能作为人类乳腺癌的不良生物标志物。此外，体外靶向ERRα的小干扰RNA（siRNA）显著降低ER阴性MDA-MB-231细胞（BLBC细胞系）的迁移，并抑制异种移植模型中的体内肿瘤生长（Stein et al.，2008年）。推测ERRα可能与雌激素反应元件（ER）结合，参与ER阴性肿瘤的雌激素介导的信号通路。因此，ERRα被认为是治疗乳腺癌（包括ER阴性乳腺癌）的潜在靶点（Misawa & Inoue，2015）。尽管ERRα被认为是孤儿核受体，但胆固醇可能是ERRα的天然配体（Wei等人，2016年）。配体结合口袋（LBP）和辅激活因子结合位点均位于ERRα LBD中。LBP充满氨基酸，留下约100 μ 3可用于配体结合。PGC-1α在共激活因子结合位点与ERRα结合并介导反式激活。ERRα被发现是组成型活性的，这是由于残基Phe 328部分填充LBP，从而允许Helix 12呈现能够...
Estrogen-related receptors (ERRs), including ERRα, ERRβ, and ERRγ, are members of nuclear receptor (NR) superfamily. ERRs have long been classified as orphan receptors because they do not bind to endogenous estrogen or any known natural ligands. However, the latest research showed that cholesterol might be its endogenous ligand (Wei et al., 2016). ERRα and ERRβ were firstly identified using the DNA-binding domain (DBD) of ERs as a hybridization probe to screen recombinant DNA libraries in 1988 (Giguere, Yang, Segui, & Evans, 1988), while ERRγ was reported later on (Eudy et al., 1998). ERRα is expressed predominately in metabolically active tissues such as intestine, brown adipose tissue, and skeletal muscles. ERRβ plays a critical role in early development, but its expression is highly restricted in adult stages and it can only be detected at low levels in adult eyes, inner ear, heart, and kidneys. The exact function of ERRγ remains unknown, but it is mainly expressed in the spinal cord and central nervous system (Heard, Norby, Holloway, & Vissing, 2000). Genetic and functional analysis demonstrates that ERRα is a critical regulator of mitochondrial biogenesis and plays a central role in the regulation of expression of energy metabolism genes involved in tricarboxylic acid (TCA) metabolism, oxidative phosphorylation (OXPHOS), and glycolysis by interacting with coactivator peroxisome proliferator-activated receptor γ coactivators (PGC-1) and corepressor nuclear receptor-interacting protein 140 (RIP-140)(Giguere, 2008). The downstream target genes of ERRα are PGC-1α (Liu & Lin, 2011), medium-chain acyl-coenzyme A dehydrogenase (MCAD)(Sladek, Bader, & Giguere, 1997), pyruvate dehydrogenase kinase 4 (PDK4)(Wende, Huss, Schaeffer, Giguere, & Kelly, 2005), and ERRα (Villena & Kralli, 2008). Notably, the high homology between the classical estrogen receptors (ERs) and ERRs provides a structural basis for the involvement of ERRs in ER signaling pathway. ERRα and ERα share some common target genes (such as pS2, lactoferrin, and osteopontin) with functional cross-talk at multiple steps of transcriptional process. These imply that ERRα may be involved in estrogen-dependent diseases, including breast, ovary, and colon cancer. For estrogen related but independent tumors, such as triple-negative and basal-like breast cancer (BLBC), the traditional hormone therapies are ineffective. However, ERRα is over expressed in ER-negative breast cancer and it could serve as a poor biomarker in human breast cancer. In addition, small interfering RNA (siRNA)-targeting ERRα in vitro substantially reduced the migration of the ER-negative MDA-MB-231 cells, a BLBC cell line, and suppressed tumor growth in vivo in an xenograft model (Stein et al., 2008). It was speculated that ERRα could bind to estrogen response element (ERE), and then participate in estrogen-mediated signaling pathway in ER-negative cancer. Therefore, ERRα has been considered as a potential target for the treatment of breast cancer, including ER-negative breast cancer (Misawa & Inoue, 2015). Although ERRα has been considered as an orphan nuclear receptor, cholesterol might be the natural ligand of ERRα (Wei et al., 2016). Both of the ligand-binding pocket (LBP) and coactivator binding site are in ERRα LBD. LBP is filled with amino acids, leaving about 100 Å3 available for ligand binding. PGC-1α binds to ERRα at the coactivator binding site and mediates transactivation. ERRα was found to be constitutively active caused by the fact that the residue Phe328 partially fills the LBP, thus allowing Helix12 to assume an active conformation capable of …