2. Academic Validation
  3. 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

  • J Med Chem. 2021 Jul 8;64(13):9217-9237. doi: 10.1021/acs.jmedchem.1c00466.
Xuewu Liang 1 2,  Chenxia Sun 3 4,  Chunpu Li 1 2,  Haolan Yu 3 4,  Xiaohui Wei 1 2,  Xuyi Liu 1 2,  Wei Bao 3 4,  Yuqiang Shi 1 2,  Xiaochen Sun 3 4,  Mirzadavlat Khamrakulov 1 2,  Chenghua Yang 3 4,  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, 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.
PMID: 34181850 DOI: 10.1021/acs.jmedchem.1c00466
Abstract

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.

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