Kinases in cerebral cavernous malformations: Pathogenesis and therapeutic targets |
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| Institution: | 1. Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, 300070, China;2. Medicinal Chemistry Theme, Monash Institute of Pharmaceutical Sciences, Australian Translational Medicinal Chemistry Facility (ATMCF), Monash University, Parkville, Victoria, Australia;3. School of Pharmaceutical Sciences, Nanjing Tech University, No. 30 South Puzhu Road, Nanjing 211816, China;1. Division of Biotechnology, Department of Applied Sciences, University of Technology, Baghdad 10066, Iraq;2. Al-Kindy College of Medicine, University of Baghdad, Baghdad, Iraq;3. Department of Pharmacy, Al-Mustaqbal University College, Babylon, Iraq;4. Department of Dentistry, Al-Farahidi University, Baghdad, Iraq;5. Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Qassim University, Qassim 51452, Kingdom of Saudi Arabia;6. Department of Pharmacognosy and Medicinal Plants, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt;1. Advanced Research Facilities & Services, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan;2. Department of Molecular Biology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan;3. Laboratory Animal Facilities & Services, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan;4. Department of Anatomy, Ultrastructural Cell Biology, Faculty of Medicine, University of Miyazaki, Miyazaki-City, Miyazaki 889-1692, Japan;5. Laboratory of Genome Stress Signaling, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan;1. Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu Province, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China;2. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China;3. Child Mental Health Research Center, The Affiliated Brain Hospital of Nanjing Medical University, Nanjing, Jiangsu, China;4. Institute for Stem Cell and Neural Regeneration, State Key Laboratory of Reproductive Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, China |
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| Abstract: | Cerebral cavernous malformations (CCMs) are low-flow, hemorrhagic vascular lesions of the central nervous system of genetic origin, which can cause stroke-like symptoms and seizures. From the identification of CCM1, CCM2 and CCM3 as genes related to disease progression, molecular and cellular mechanisms for CCM pathogenesis have been established and the search for potential drugs to target CCM has begun. Broadly speaking, kinases are the major group signaling in CCM pathogenesis. These include the MEKK3/MEK5/ERK5 cascade, Rho/Rock signaling, CCM3/GCKIII signaling, PI3K/mTOR signaling, and others. Since the discovery of Rho/Rock in CCM pathogenesis, inhibitors for Rho signaling and subsequently other components in CCM signaling were discovered and applied in preclinical and clinical trials to ameliorate CCM progression. This review discusses the general aspects of CCM disease, kinase-mediated signaling in CCM pathogenesis and the current state of potential treatment options for CCM. It is suggested that kinase target drug development in the context of CCM might facilitate and meet the unmet requirement – a non-surgical option for CCM disease. |
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