新型肺癌靶向的组蛋白赖氨酸特异性去甲基化酶LSD1抑制剂和降解剂的设计、合成及其抗肿瘤活性评价

Histone lysine specific demethylase 1 (LSD1) is overexpressed in lung tissues and closely related with tumor proliferation, evasion, migration, and poor prognosis, inactivation or down-regulation of LSD1 by small molecules or RNAi leads to inhibition of proliferation, migration and evasion. Three irreversible LSD1 inhibitors, namely ORY-1001, GSK-2879552, and INCB059872, have advanced into clinical trials for the treatment of AML and SCLC, while no reversible LSD1 inhibitors are currently investigated in clinical trials. Following our previous work on LSD1, we intend to carry out the following work: (1) Design of new LSD1 inhibitors employing the high throughput virtual screening and structure-based drug design strategies, and then to establish the small-molecule library of LSD1 with structural diversity and complexity based on the bioisosteric replacement and scaffold hopping methods; (2). We also plan to design novel LSD1 protein degraders based on the PROTACs strategy and to explore the feasibility of LSD1 degraders for the treatment of lung cancer. In this project, we are expecting to obtain 2-3 highly potent and selective small-molecule compounds targeting LSD1 through multi-level activity evaluation, and mechanistic investigations, hoping to provide evidence for the design of novel anticancer drugs targeting LSD1.

组蛋白赖氨酸特异性去甲基化酶LSD1在肺癌组织中高表达且与肿瘤增殖、侵袭与转移及不良预后密切相关，小分子抑制剂或RNAi介导的LSD1抑制或低表达可抑制肿瘤细胞增殖、转移和侵袭。不可逆LSD1抑制剂ORY-1001、GSK-2879552和INCB059872已进入临床试验用于治疗白血病和小细胞肺癌，而可逆LSD1抑制剂尚未进入临床阶段的研发。在前期工作基础之上，本项目拟开展：（1）、利用高通量虚拟筛选技术并结合基于结构的药物设计等方法设计新型肺癌靶向的LSD1可逆抑制剂，并通过生物电子等排和骨架跃迁等方法构建具有结构多样性和复杂性的小分子化合物库；（2）、基于PROTACs策略设计新型LSD1降解剂，并探索其用于肺癌治疗的可能性。通过分子、细胞和动物水平的抗肿瘤活性毒性评价和机制研究，期望获得2-3个高效高选择性的候选化合物，为今后探索以LSD1为靶点的抗肿瘤药物设计提供理论基础。

组蛋白赖氨酸特异性去甲基化酶LSD1是一类重要的表观调控蛋白，与肿瘤的发生发展密切相关，目前已有多个小分子抑制剂如ORY-1001等进入临床用于评估其肿瘤治疗效果，其中多数为苯环丙胺类不可逆抑制剂，可逆LSD1抑制剂只有CC-90011在临床评估阶段。鉴于苯环丙胺类化合物缺乏专一性和潜在的毒性，开发高活性高选择性类药属性好的LSD1可逆抑制剂具有较大的科学价值和临床应用前景。.本项目主要开展了以下研究内容：.(A).开发了药物及天然产物优势骨架结构如联芳基、非天然氨基酸、二肽、吲哚及类天然产物等的合成新方法，高效构建了多样性小分子化合物库；.(B).通过天然产物库筛选发现小檗碱生物碱能够有效抑制LSD1，并对表小檗碱进行了深入的抗肿瘤活性与机制评价； .(C).采用基于配体的药物设计方法，设计并合成黄嘌呤类LSD1抑制剂，并在分子和细胞水平评价了该类抑制剂的活性与机制；.(D).基于嘧啶并三氮唑和二芳基硫醚类优势骨架结构，开展了系统的构效关系研究和活性机制评价。此外，通过多样性小分子化合物库的筛选，发现了具有进一步开发前景的ABCB1和DCN1抑制剂；.(E).基于靶向蛋白降解策略，设计并合成了靶向LSD1的降解剂，探究了基于PROTACs策略设计LSD1降解剂的可行性；.通过以上研究，已获得多个高活性高选择性类药属性好的LSD1先导化合物，为今后靶向LSD1的创新药物发现提供物质基础。