Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations.
Choi, JP
Wang, R
Yang, X
Wang, X
Wang, L
Ting, KK
Foley, M
Cogger, V
Yang, Z
Liu, F
Han, Z
Liu, R
Baell, J
Zheng, X
- Publisher:
- AMER ASSOC ADVANCEMENT SCIENCE
- Publication Type:
- Journal Article
- Citation:
- Sci Adv, 2018, 4, (11), pp. eaau0731
- Issue Date:
- 2018-11
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Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Choi, JP | |
dc.contributor.author | Wang, R | |
dc.contributor.author | Yang, X | |
dc.contributor.author | Wang, X | |
dc.contributor.author | Wang, L | |
dc.contributor.author | Ting, KK | |
dc.contributor.author | Foley, M | |
dc.contributor.author | Cogger, V | |
dc.contributor.author | Yang, Z | |
dc.contributor.author | Liu, F | |
dc.contributor.author | Han, Z | |
dc.contributor.author | Liu, R | |
dc.contributor.author | Baell, J | |
dc.contributor.author | Zheng, X | |
dc.date.accessioned | 2022-09-03T21:37:54Z | |
dc.date.available | 2018-10-03 | |
dc.date.available | 2022-09-03T21:37:54Z | |
dc.date.issued | 2018-11 | |
dc.identifier.citation | Sci Adv, 2018, 4, (11), pp. eaau0731 | |
dc.identifier.issn | 2375-2548 | |
dc.identifier.issn | 2375-2548 | |
dc.identifier.uri | http://hdl.handle.net/10453/161290 | |
dc.description.abstract | Cerebral cavernous malformation (CCM) is a common cerebrovascular disease that can occur sporadically or be inherited. They are major causes of stroke, cerebral hemorrhage, and neurological deficits in the younger population. Loss-of-function mutations in three genes, CCM1, CCM2, and CCM3, have been identified as the cause of human CCMs. Currently, no drug is available to treat CCM disease. Hyperactive mitogen-activated protein kinase kinase Kinase 3 (MEKK3) kinase signaling as a consequence of loss of CCM genes is an underlying cause of CCM lesion development. Using a U.S. Food and Drug Administration-approved kinase inhibitor library combined with virtual modeling and biochemical and cellular assays, we have identified a clinically approved small compound, ponatinib, that is capable of inhibiting MEKK3 activity and normalizing expression of downstream kruppel-like factor (KLF) target genes. Treatment with this compound in neonatal mouse models of CCM can prevent the formation of new CCM lesions and reduce the growth of already formed lesions. At the ultracellular level, ponatinib can normalize the flattening and disorganization of the endothelium caused by CCM deficiency. Collectively, our study demonstrates ponatinib as a novel compound that may prevent CCM initiation and progression in mouse models through inhibition of MEKK3-KLF signaling. | |
dc.format | Electronic-eCollection | |
dc.language | eng | |
dc.publisher | AMER ASSOC ADVANCEMENT SCIENCE | |
dc.relation.ispartof | Sci Adv | |
dc.relation.isbasedon | 10.1126/sciadv.aau0731 | |
dc.rights | info:eu-repo/semantics/openAccess | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Cells, Cultured | |
dc.subject.mesh | Disease Progression | |
dc.subject.mesh | Endothelium, Vascular | |
dc.subject.mesh | Gene Expression Regulation | |
dc.subject.mesh | Imidazoles | |
dc.subject.mesh | Intellectual Disability | |
dc.subject.mesh | KRIT1 Protein | |
dc.subject.mesh | Kruppel-Like Transcription Factors | |
dc.subject.mesh | MAP Kinase Kinase Kinase 3 | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Mice, Inbred C57BL | |
dc.subject.mesh | Mice, Knockout | |
dc.subject.mesh | Microfilament Proteins | |
dc.subject.mesh | Micrognathism | |
dc.subject.mesh | Mutation | |
dc.subject.mesh | Protein Kinase Inhibitors | |
dc.subject.mesh | Pyridazines | |
dc.subject.mesh | Ribs | |
dc.subject.mesh | Signal Transduction | |
dc.subject.mesh | Zebrafish | |
dc.subject.mesh | Ribs | |
dc.subject.mesh | Endothelium, Vascular | |
dc.subject.mesh | Cells, Cultured | |
dc.subject.mesh | Animals | |
dc.subject.mesh | Mice, Inbred C57BL | |
dc.subject.mesh | Mice, Knockout | |
dc.subject.mesh | Zebrafish | |
dc.subject.mesh | Mice | |
dc.subject.mesh | Micrognathism | |
dc.subject.mesh | Disease Progression | |
dc.subject.mesh | Imidazoles | |
dc.subject.mesh | Pyridazines | |
dc.subject.mesh | Microfilament Proteins | |
dc.subject.mesh | MAP Kinase Kinase Kinase 3 | |
dc.subject.mesh | Protein Kinase Inhibitors | |
dc.subject.mesh | Signal Transduction | |
dc.subject.mesh | Gene Expression Regulation | |
dc.subject.mesh | Mutation | |
dc.subject.mesh | Kruppel-Like Transcription Factors | |
dc.subject.mesh | Intellectual Disability | |
dc.subject.mesh | KRIT1 Protein | |
dc.title | Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations. | |
dc.type | Journal Article | |
utslib.citation.volume | 4 | |
utslib.location.activity | United States | |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science/School of Life Sciences | |
utslib.copyright.status | open_access | * |
dc.date.updated | 2022-09-03T21:37:47Z | |
pubs.issue | 11 | |
pubs.publication-status | Published online | |
pubs.volume | 4 | |
utslib.citation.issue | 11 |
Abstract:
Cerebral cavernous malformation (CCM) is a common cerebrovascular disease that can occur sporadically or be inherited. They are major causes of stroke, cerebral hemorrhage, and neurological deficits in the younger population. Loss-of-function mutations in three genes, CCM1, CCM2, and CCM3, have been identified as the cause of human CCMs. Currently, no drug is available to treat CCM disease. Hyperactive mitogen-activated protein kinase kinase Kinase 3 (MEKK3) kinase signaling as a consequence of loss of CCM genes is an underlying cause of CCM lesion development. Using a U.S. Food and Drug Administration-approved kinase inhibitor library combined with virtual modeling and biochemical and cellular assays, we have identified a clinically approved small compound, ponatinib, that is capable of inhibiting MEKK3 activity and normalizing expression of downstream kruppel-like factor (KLF) target genes. Treatment with this compound in neonatal mouse models of CCM can prevent the formation of new CCM lesions and reduce the growth of already formed lesions. At the ultracellular level, ponatinib can normalize the flattening and disorganization of the endothelium caused by CCM deficiency. Collectively, our study demonstrates ponatinib as a novel compound that may prevent CCM initiation and progression in mouse models through inhibition of MEKK3-KLF signaling.
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