Target basierte Entwicklung neuer Hemmstoffe der Lysin-Dementhylase LSDI und deren Einfluss auf die Regulation des Androgenrezeptors

新型赖氨酸脱甲基酶LSDI抑制剂的靶向开发及其对雄激素受体调节的影响

• 批准号: 93713832
• 负责人: Professor Dr. Manfred Jung
• 金额: --
• 依托单位: Abteilung Medizinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/93713832?language=en
• 关键词: Target; basierte; Entwicklung; neuer; Hemmstoffe

Histone modifying enzymes are key players of the epigenetic regulation in eukaryotic cells. The lysine specific demethylase 1 (LSD1) demethylates histone proteins and is a higly promising target for combatting prostate cancer. Disovery and development of new LSD1 inhibitors are still rather limited. In this project we have developed new potent LSD1 inhibitors with cellular activity through a combination of virtual screening, biological testing and medicinal chemistry. A highlight is the reversible LSD1 inhibitor namoline that blocks prostate cancer growth in vivo. In this proposal we want to provided new selective LSD1 inhibitors with improved anticancer activity in vitro and in vivo. We will combine lead structure guided medicinal chemistry, structure based molecular modelling and advanced preclinical models. New inhibitors will be tested in cells for their effects on androgen dependent transcription and growth. Inhibitors with high cellular activity are candidates for animal testing in genetically modified animals and in vivo-tumor models. The impact of the inhibitors on histone modifications on a genome wide scale is an important part of this project. This investigations will lead to an improved understanding of the biological role of LSD1 and its therapeutic potential and provide potential drug candidates for cancer therapy.

组蛋白修饰酶是真核细胞表观遗传调控的关键酶。赖氨酸特异性去甲基化酶1（LSD 1）使组蛋白去甲基化，是一个非常有前途的治疗前列腺癌的靶点。新的LSD 1抑制剂的发现和开发仍然相当有限。在这个项目中，我们通过虚拟筛选、生物测试和药物化学的结合，开发了具有细胞活性的新型强效LSD 1抑制剂。一个亮点是可逆的LSD 1抑制剂namoline，它可以在体内阻断前列腺癌的生长。在该提议中，我们希望提供具有改善的体外和体内抗癌活性的新的选择性LSD 1抑制剂。我们将结合联合收割机领导结构指导的药物化学，基于结构的分子建模和先进的临床前模型。新的抑制剂将在细胞中测试其对雄激素依赖性转录和生长的影响。具有高细胞活性的抑制剂是在转基因动物和体内肿瘤模型中进行动物试验的候选物。抑制剂对全基因组范围内组蛋白修饰的影响是该项目的重要组成部分。这项研究将有助于更好地了解LSD 1的生物学作用及其治疗潜力，并为癌症治疗提供潜在的候选药物。