2. Academic Validation
  3. Development of Potent MALT1 Inhibitors Featuring a Novel "2-Thioxo-2,3-dihydrothiazolo[4,5- d]pyrimidin-7(6 H)-one" Scaffold for the Treatment of B Cell Lymphoma

Development of Potent MALT1 Inhibitors Featuring a Novel "2-Thioxo-2,3-dihydrothiazolo[4,5- d]pyrimidin-7(6 H)-one" Scaffold for the Treatment of B Cell Lymphoma

  • J Med Chem. 2024 Feb 22;67(4):2884-2906. doi: 10.1021/acs.jmedchem.3c02031.
Xuewu Liang 1 2,  Haolan Yu 3 4,  Renwen Liang 1 2,  Zhuanghui Feng 3,  Abdusaid Saidahmatov 1 2,  Chenxia Sun 3 4,  Hairu Ren 1 2 5,  Xiaohui Wei 1 2,  Jiayan Zhao 1 2 5,  Chenghua Yang 3 6,  Hong Liu 1 2 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 2 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3 Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200043, China.
  • 4 CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
  • 5 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 6 Shanghai Key Laboratory of Cell Engineering, Shanghai 200433, China.
PMID: 38349664 DOI: 10.1021/acs.jmedchem.3c02031
Abstract

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.

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