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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 mu M. 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.