Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma.
Identification of Novel Fused Heteroaromatics-Based MALT1 Inhibitors by High-Throughput Screening to Treat B Cell Lymphoma.
复制标题
通过高通量筛选鉴定新型融合杂芳族化合物 MALT1 抑制剂，用于治疗 B 细胞淋巴瘤。
DOI：
10.1021/acs.jmedchem.1c00466
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发表时间：
2021-06
影响因子：
7.3
通讯作者：
Hong Liu
中科院分区：
文献类型：
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作者：
Xuewu Liang;Chenxia Sun;Chunpu Li;Haolan Yu;Xiaohui Wei;Xuyi Liu;Wei Bao;Yuqiang Shi;Xiaochen Sun;Mirzadavlat Khamrakulov;Chenghua Yang;Hong Liu
黏膜相关淋巴组织淋巴瘤易位蛋白1 （MALT1）抑制剂的开发在肿瘤疾病、炎症和自身免疫性疾病的治疗中具有重要的价值和意义。然而，临床上缺乏有效的MALT1抑制剂。本文通过高通量筛选，首次鉴定并设计了一类新型有效的5-氧-1-硫氧-4,5-二氢- 1h -噻唑[3,4-a]喹唑啉类MALT1抑制剂及其共价衍生物。我们证明了化合物15c、15e和20c有效抑制MALT1蛋白酶，并对具有低个位数微摩尔效价的活化B细胞样弥漫性大B细胞淋巴瘤表现出选择性细胞毒性。此外，化合物20c在malt1依赖的TMD8细胞中特异性抑制NF-κB信号并诱导细胞凋亡，且呈剂量依赖性。更重要的是，20c在TMD8异种移植肿瘤模型中表现出良好的药动学特性和抗肿瘤功效，且无明显毒性。总之，本研究为进一步优化MALT1抑制剂的结构和抗肿瘤机制研究提供了有价值的先导化合物。
Development of mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) inhibitors is of great value and significance in the treatment of neoplastic disorders and inflammatory and autoimmune diseases. However, there is a lack of effective MALT1 inhibitors in clinic. Herein, a novel class of potent 5-oxo-1-thioxo-4,5-dihydro-1H-thiazolo[3,4-a]quinazoline-based MALT1 inhibitors and their covalent derivatives were first identified and designed through high-throughput screening. We demonstrated that compounds 15c, 15e, and 20c effectively inhibited the MALT1 protease and displayed selective cytotoxicity to activated B cell-like diffuse large B cell lymphoma with low single-digit micromolar potency. Furthermore, compound 20c specifically repressed NF-κB signaling and induced cell apoptosis in MALT1-dependent TMD8 cells in a dose-dependent manner. More importantly, 20c showed good pharmacokinetic properties and antitumor efficacy with no significant toxicity in the TMD8 xenograft tumor model. Collectively, this study provides valuable lead compounds of MALT1 inhibitors for further structural optimization and antitumor mechanism study.