新型维生素D受体-共激活因子抑制剂的研发
Development of novel Vitamin D Receptor-Coactivator Inhibitors.
作者信息
Sidhu Preetpal S, Nassif Nicholas, McCallum Megan M, Teske Kelly, Feleke Belaynesh, Yuan Nina Y, Nandhikonda Premchendar, Cook James M, Singh Rakesh K, Bikle Daniel D, Arnold Leggy A
机构信息
Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, WI 53211, USA.
Molecular Therapeutics Laboratory, Program in Women's Oncology, Department of Obstetrics and Gynecology, Woman and Infant's Hospital of Rhode Island, Alpert Medical School of, Brown University, Provence, Rhode Island, USA.
出版信息
ACS Med Chem Lett. 2014 Feb 13;5(2):199-204. doi: 10.1021/ml400462j.
Nuclear receptor coregulators are master regulators of transcription and selectively interact with the vitamin D receptor (VDR) to modulate cell differentiation, cell proliferation and calcium homeostasis. Herein, we report the syntheses and evaluation of highly potent and selective VDR-coactivator inhibitors based on a recently identified 3-indolylmethanamine scaffold. The most active compound, PS121912, selectively inhibited VDR-mediated transcription among eight other nuclear receptors tested. PS121912 is also selectively disrupting the binding between VDR and the third nuclear receptor interaction domain of the coactivator SRC2. Genetic studies revealed that PS121912 behaves like a VDR antagonist by repressing 1,25-(OH)D activated gene transcription. In addition, PS121912 induced apoptosis in HL-60.
核受体共调节因子是转录的主要调节因子，可与维生素D受体（VDR）选择性相互作用，以调节细胞分化、细胞增殖和钙稳态。在此，我们报告了基于最近鉴定的3-吲哚基甲胺支架的高效和选择性VDR共激活剂抑制剂的合成与评价。活性最高的化合物PS121912在测试的其他八种核受体中选择性抑制VDR介导的转录。PS121912还选择性地破坏VDR与共激活剂SRC2的第三个核受体相互作用域之间的结合。遗传学研究表明，PS121912通过抑制1,25-(OH)D激活的基因转录，表现得像一种VDR拮抗剂。此外，PS121912诱导HL-60细胞凋亡。
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