CRAC channels as targets for drug discovery and development |
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| Affiliation: | 1. Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, Wales, UK;2. Department of Physiology, Medical College, Jinan University, Guangzhou 510632, China;1. Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid y Consejo Superior de Investigaciones Científicas (CSIC), Valladolid, Spain;2. Departamento de Bioquímica STIM Biología Molecular STIM Fisiología, Universidad de Valladolid, Valladolid, Spain;1. The School of Pharmacy, The University of Queensland, Brisbane, Queensland, Australia;2. Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia;3. Translational Research Institute, Brisbane, Queensland, Australia;4. Auckland Cancer Society Research Centre, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;5. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand;6. Institute for Molecular Bioscience, The University of Queensland, St Lucia, Queensland 4072, Australia;7. School of Pharmacy, The University of Queensland, Woolloongabba, Queensland 4102, Australia;1. Institute of Biophysics, Johannes Kepler University Linz, Gruberstrasse 40, 4020 Linz, Austria;2. Institute of Biochemistry and Molecular Medicine, University of Bern, Buehlstrasse 28, CH-3012 Bern, Switzerland;3. Gottfried Schatz Forschungszentrum, Medizinische Universität Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria;1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China;2. College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX, USA;3. Comprehensive Cancer Center, The Ohio State University Medical Center, Columbus, OH, USA;4. Rhizen Pharmaceuticals SA, La Chaux-de-Fonds, Switzerland;5. Incozen Therapeutics Private Limited, Hyderabad, India;6. Department of Biology, University of Texas at Arlington, Arlington, TX, USA;7. Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, Henan, China;1. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States;2. Department of Laboratory Medicine, University of California, San Francisco, CA, United States |
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| Abstract: | Calcium release-activated calcium (CRAC) channels have been the target of drug discovery for many years. The identification of STIM and Orai proteins as key components of CRAC channels greatly facilitated this process because their co-expression in cell lines produced electrophysiological currents (ICRAC) much larger than those in native cells, making it easier to confirm and characterize the effects of modulatory compounds. A driving force in the quest for CRAC channel drugs has been the immunocompromised phenotype displayed by humans and mice with null or loss-of-function mutations in STIM1 or Orai1, suggesting that CRAC channel inhibitors could be useful therapeutics for autoimmune or inflammatory conditions. Emerging data also suggests that other therapeutic conditions may benefit from CRAC channel inhibition. However, only recently have CRAC channel inhibitors reached clinical trials. This review discusses the challenges associated with drug discovery and development on CRAC channels and the approaches employed to date, as well as the results, starting from initial high-throughput screens for CRAC channel modulators and progressing through target selection and justification, descriptions of pharmacological, safety and toxicological profiles of compounds, and finally the entry of CRAC channel inhibitors into clinical trials. |
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| Keywords: | CRAC channel STIM Orai Store-operated calcium entry Pharmacology Toxicology Therapeutics |
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