Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations

Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1126/sciadv.aau0731
Journal or Publication Title: Science Advances
Volume: 4
Number: 11
Page Range: eaau0731
Date: 2018
Divisions: Cell Signalling
Vascular Biology
Depositing User: General Admin
Identification Number: 10.1126/sciadv.aau0731
ISSN: 2375-2548
Date Deposited: 03 Jan 2021 22:29
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.

Creators:
Creators
Email
Choi, Jaesung P.
UNSPECIFIED
Wang, Rui
UNSPECIFIED
Yang, Xi
UNSPECIFIED
Wang, Xian
UNSPECIFIED
Wang, Lu
UNSPECIFIED
Ting, Ka Ka
UNSPECIFIED
Foley, Matthew
UNSPECIFIED
Cogger, Victoria
UNSPECIFIED
Yang, Zhuo
UNSPECIFIED
Liu, Feng
UNSPECIFIED
Han, Zhiming
UNSPECIFIED
Liu, Renjing
UNSPECIFIED
Baell, Jonathan
UNSPECIFIED
Zheng, Xiangjian
UNSPECIFIED
Last Modified: 03 Jan 2021 22:29
URI: https://eprints.centenary.org.au/id/eprint/553

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