Discovery and optimization of a series of small-molecule allosteric inhibitors of MALT1 protease期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

Discovery and optimization of a series of small-molecule allosteric inhibitors of MALT1 protease

Affiliation:	1. Janssen Research & Development, LLC, 1400 McKean Road, Spring House, PA 19477, United States;2. Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium;1. Xinjiang Production & Construction Corps Key Laboratory of Protection and Utilization of Biological Resources in Tarim Basin, Tarim University, Alaer 843300, China;2. College of Plant Protection, State & Local Joint Engineering Research Center of Green Pesticide Invention and Application, Nanjing Agricultural University, Nanjing 210095, China;1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, China;2. Department of Clinical Laboratory, The 309th Hospital of Chinese People’s Liberation Army, Beijing 100091, China;1. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100050, China;2. Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100050, China;3. China National Clinical Research Center for Neurological Diseases, Beijing, 100050, China;4. Chinese Glioma Cooperative Group (CGCG), China;1. Program in Cell Death and Survival Networks, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA;2. Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA;1. Centre for Blood Research, Life Sciences Centre, University of British Columbia, Vancouver, BC V6T 1Z3, Canada;2. Department of Oral Biological and Medical Sciences, Faculty of Dentistry, University of British Columbia, Vancouver, BC V6T 1Z3, Canada;3. Department of Immunology, Eberhard Karl University Tübingen, 72076 Tübingen, Germany;4. Novartis Institutes for BioMedical Research, Novartis Campus, CH-4056 Basel, Switzerland;5. Department of Pediatrics, British Columbia Children''s Hospital, The University of British Columbia, Vancouver, BC V5Z 4H4, Canada;6. Department of Experimental Medicine, Faculty of Medicine, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada;7. Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of British Columbia, Vancouver, BC V6T 1Z3, Canada;8. Department of Hematology and Oncology, University Hospital Tübingen, Children''s Hospital, 72076 Tübingen, Germany;9. Molecular Targeted Therapy - Discovery Oncology, Roche Pharma Research & Early Development, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland

Abstract:	We describe a series of potent and highly selective small-molecule MALT1 inhibitors, optimized from a High-Throughput Screening hit. Advanced analogues such as compound 40 show high potency (IC₅₀: 0.01 µM) in a biochemical assay measuring MALT1 enzymatic activity, as well as in cellular assays: Jurkat T cell activation (0.05 µM) and IL6/10 secretion (IC₅₀: 0.10/0.06 µM) in the TMD8 B-cell lymphoma line. Compound 40 also inhibited cleavage of the MALT1 substrate RelB (IC₅₀: 0.10 µM). Mechanistic enzymology results suggest that these compounds bind to the known allosteric site of the protease.

Keywords:	MALT1 Paracaspase Allosteric inhibitors Autoimmune diseases Discovery and optimization
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