Grasberger Bruce L, Lu Tianbao, Schubert Carsten, Parks Daniel J, Carver Theodore E, Koblish Holly K, Cummings Maxwell D, LaFrance Louis V, Milkiewicz Karen L, Calvo Raul R, Maguire Diane, Lattanze Jennifer, Franks Carol F, Zhao Shuyuan, Ramachandren Kannan, Bylebyl Gwendolyn R, Zhang Marie, Manthey Carl L, Petrella Eugene C, Pantoliano Michael W, Deckman Ingrid C, Spurlino John C, Maroney Anna C, Tomczuk Bruce E, Molloy Christopher J, Bone Roger F
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 665 Stockton Drive, Exton, Pennsylvania 19341, USA.
J Med Chem. 2005 Feb 24;48(4):909-12. doi: 10.1021/jm049137g.
HDM2 binds to an alpha-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2-p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their alpha-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.
HDM2与p53的α-螺旋反式激活结构域结合，抑制其肿瘤抑制功能。采用小型化热变性分析筛选化学文库，发现了一系列新型的HDM2-p53相互作用的苯并二氮杂䓬二酮拮抗剂。与HDM2结合的改良拮抗剂的X射线晶体结构揭示了它们的α-螺旋模拟特性。这些优化的分子增加了p53靶基因的转录，并减少了表达野生型p53的肿瘤细胞的增殖。
