Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) has emerged as a novel and promising therapeutic target for the treatment of lymphomas and autoimmune diseases. Herein, we reported a new class of MALT1 inhibitors featuring a novel “2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one” scaffold developed by structure-based drug design. Structure–activity relationship studies finally led to the discovery of MALT1 inhibitor 10m, which covalently and potently inhibited MALT1 protease with the IC₅₀ value of 1.7 μM. 10m demonstrated potent and selective antiproliferative activity against ABC-DLBCL and powerful ability to induce HBL1 apoptosis. 10m also effectively downregulated the activities of MALT1 and its downstream signal pathways. Furthermore, 10m induced upregulation of mTOR and PI3K-Akt signals and exhibited a synergistic antitumor effect with Rapamycin in HBL1 cells. More importantly, 10m remarkably suppressed the tumor growth both in the implanted HBL1 and TMD8 xenograft models. Collectively, this work provides valuable MALT1 inhibitors with a distinct core structure.

中文翻译：

---

开发具有新型“2-Thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-one”支架的强效 MALT1 抑制剂，用于治疗 B 细胞淋巴瘤

粘膜相关淋巴组织淋巴瘤易位蛋白 1 (MALT1) 已成为治疗淋巴瘤和自身免疫性疾病的新型且有前景的治疗靶点。在此，我们报道了一类新型 MALT1 抑制剂，其特征是通过基于结构的药物设计开发的新型“2-thioxo-2,3-dihydrothiazolo[4,5- d ]pyrimidin-7(6 H )-one”支架。构效关系研究最终发现了MALT1抑制剂10m，它能共价有效抑制MALT1蛋白酶，IC ₅₀值为1.7 μM。10m表现出针对 ABC-DLBCL 的有效且选择性的抗增殖活性以及诱导 HBL1 凋亡的强大能力。10m还有效下调MALT1及其下游信号通路的活性。此外，10m诱导 mTOR 和 PI3K-Akt 信号上调，并在 HBL1 细胞中与雷帕霉素表现出协同抗肿瘤作用。更重要的是，10m显着抑制了植入的 HBL1 和 TMD8 异种移植模型中的肿瘤生长。总的来说，这项工作提供了具有独特核心结构的有价值的 MALT1 抑制剂。