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

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

Permalink

Publisher:: AMER ASSOC ADVANCEMENT SCIENCE
Publication Type:: Journal Article
Citation:: Sci Adv, 2018, 4, (11), pp. eaau0731
Issue Date:: 2018-11

Open Access

Copyright Clearance Process

Recently Added
In Progress
Open Access

This item is open access.

Adobe PDF

Download Published versionAdobe PDF (1.77 MB)

View on publisher's site

View statistics

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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/161290