Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease
Kinases are an intensively studied drug target class in current pharmacological research as evidenced by the large number of kinase inhibitors being assessed in clinical trials. Kinase-targeted therapies have potential for treatment of a broad array of indications including central nervous system (C...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-09-01
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| Series: | Frontiers in Aging Neuroscience |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fnagi.2020.00242/full |
| _version_ | 1818846430366793728 |
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| author | Caroline L. Benn Lee A. Dawson |
| author_facet | Caroline L. Benn Lee A. Dawson |
| author_sort | Caroline L. Benn |
| collection | DOAJ |
| description | Kinases are an intensively studied drug target class in current pharmacological research as evidenced by the large number of kinase inhibitors being assessed in clinical trials. Kinase-targeted therapies have potential for treatment of a broad array of indications including central nervous system (CNS) disorders. In addition to the many variables which contribute to identification of a successful therapeutic molecule, drug discovery for CNS-related disorders also requires significant consideration of access to the target organ and specifically crossing the blood-brain barrier (BBB). To date, only a small number of kinase inhibitors have been reported that are specifically designed to be BBB permeable, which nonetheless demonstrates the potential for success. This review considers the potential for kinase inhibitors in the context of unmet medical need for neurodegenerative disease. A subset of kinases that have been the focus of clinical investigations over a 10-year period have been identified and discussed individually. For each kinase target, the data underpinning the validity of each in the context of neurodegenerative disease is critically evaluated. Selected molecules for each kinase are identified with information on modality, binding site and CNS penetrance, if known. Current clinical development in neurodegenerative disease are summarized. Collectively, the review indicates that kinase targets with sufficient rationale warrant careful design approaches with an emphasis on improving brain penetrance and selectivity. |
| first_indexed | 2024-12-19T05:45:26Z |
| format | Article |
| id | doaj.art-0671bb57043248d799699a2d556865be |
| institution | Directory Open Access Journal |
| issn | 1663-4365 |
| language | English |
| last_indexed | 2024-12-19T05:45:26Z |
| publishDate | 2020-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj.art-0671bb57043248d799699a2d556865be2022-12-21T20:33:52ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652020-09-011210.3389/fnagi.2020.00242564475Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative DiseaseCaroline L. Benn0Lee A. Dawson1LoQus23 Therapeutics, Cambridge, United KingdomCerevance Ltd., Cambridge, United KingdomKinases are an intensively studied drug target class in current pharmacological research as evidenced by the large number of kinase inhibitors being assessed in clinical trials. Kinase-targeted therapies have potential for treatment of a broad array of indications including central nervous system (CNS) disorders. In addition to the many variables which contribute to identification of a successful therapeutic molecule, drug discovery for CNS-related disorders also requires significant consideration of access to the target organ and specifically crossing the blood-brain barrier (BBB). To date, only a small number of kinase inhibitors have been reported that are specifically designed to be BBB permeable, which nonetheless demonstrates the potential for success. This review considers the potential for kinase inhibitors in the context of unmet medical need for neurodegenerative disease. A subset of kinases that have been the focus of clinical investigations over a 10-year period have been identified and discussed individually. For each kinase target, the data underpinning the validity of each in the context of neurodegenerative disease is critically evaluated. Selected molecules for each kinase are identified with information on modality, binding site and CNS penetrance, if known. Current clinical development in neurodegenerative disease are summarized. Collectively, the review indicates that kinase targets with sufficient rationale warrant careful design approaches with an emphasis on improving brain penetrance and selectivity.https://www.frontiersin.org/article/10.3389/fnagi.2020.00242/fullinhibitorcentral nervous systemATPsmall moleculeclinical developmentblood brain barrier |
| spellingShingle | Caroline L. Benn Lee A. Dawson Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease Frontiers in Aging Neuroscience inhibitor central nervous system ATP small molecule clinical development blood brain barrier |
| title | Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease |
| title_full | Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease |
| title_fullStr | Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease |
| title_full_unstemmed | Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease |
| title_short | Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease |
| title_sort | clinically precedented protein kinases rationale for their use in neurodegenerative disease |
| topic | inhibitor central nervous system ATP small molecule clinical development blood brain barrier |
| url | https://www.frontiersin.org/article/10.3389/fnagi.2020.00242/full |
| work_keys_str_mv | AT carolinelbenn clinicallyprecedentedproteinkinasesrationalefortheiruseinneurodegenerativedisease AT leeadawson clinicallyprecedentedproteinkinasesrationalefortheiruseinneurodegenerativedisease |