Abstract：
Histone lysine specific demethylase 1 (LSD1) is responsible for the demethylation of mono-/dimethylated lysine residue on histone proteins. LSD1 plays an extensive and essential role in the pathogenesis and progression of many human diseases such as cancers, and thus is becoming an attractive therapeutic target for cancer treatment. Tranylcypromine (TCP) is an important chemical template for developing irreversible LSD1 inhibitors, representing a major chemotype of clinical candidates. Here we report a novel pool of TCP derivatives with triazolopyrimidine as a privileged heterocylic motif. Starting from ticagrelor, a clinically available antiplatelet agent, as a hit compound, our medicinal efforts have led to the identification of compound 9j with nanomolar inhibitory potency against LSD1 as well as broad-spectrum antiproliferative activities against tumor cells. Enzyme studies show that compound 9j is selective over MAO-A/B enzymes, and also cellular active to elevate the expression of H3K4me2 by inhibiting LSD1 in cells. Furthermore, in a H1650 xenograft mouse model, oral administration of compound 9j at low 10 and 20 mg/kg dosages could enable a significant reduction in tumor size and a remarkable extension of survival. The current work is expected to provide an additional strategy to achieve new TCP-based LSD1 inhibitors.
摘要：
组蛋白赖氨酸特异性去甲基酶1(LSD1)负责组蛋白上的单/二甲基化赖氨酸残基的去甲基化。LSD1在许多人类疾病（如癌症）的发病机制和进展中起着广泛而重要的作用。因此正成为癌症治疗的一个有吸引力的治疗靶点。环丙胺(TCP)是开发不可逆LSD1抑制剂的重要化学模板,代表临床候选人的主要化学类型。在这里，我们报告了一种新型的TCP衍生物库，其中三唑并嘧啶作为特权杂环基序。从替格瑞洛开始,临床上可用的抗血小板药物，作为一个热门化合物，我们的药物努力已导致化合物9j的鉴定具有纳摩尔对LSD1的抑制效力以及对肿瘤细胞的广谱抗增殖活性。酶研究表明，化合物9j对MAO-A/B酶具有选择性，并且还具有细胞活性以通过抑制细胞中的LSD1来提高H3K4me2的表达。此外，在H1650异种移植小鼠模型中，以10mg/kg和20mg/kg低剂量口服给药化合物9j可以实现肿瘤大小的显著减小和存活的显著延长。目前的工作有望提供一种额外的策略来实现新的基于TCP的LSD1抑制剂。
