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Drug for preventing and treating cerebral cavernous malformation (CCM)

A brain spongy and malformation technology, applied in the field of medicine for preventing and treating cerebral cavernous malformation lesions

Active Publication Date: 2020-01-17
TIANJIN MEDICAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But, despite this, the art still has not found a drug suitable for the treatment of this disease

Method used

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  • Drug for preventing and treating cerebral cavernous malformation (CCM)
  • Drug for preventing and treating cerebral cavernous malformation (CCM)
  • Drug for preventing and treating cerebral cavernous malformation (CCM)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Example 1, Ponatinib directly inhibits MEKK3 kinase activity

[0112] The inventors performed complex protein modeling based on crystal structures and performed in vitro kinase assays using purified MEKK3 and its interacting substrates and its kinase substrate MEK5. Ponatinib is a type II kinase inhibitor that binds the kinase in the DFG-out conformation. Based on the previously solved crystal structure of the Ponatinib-FGFR4 complex, the Ponatinib-Abl complex and the structure-solved DFG-out kinase PAK1 with high homology to the MEKK3 kinase domain, computer modeling reveals that in the ATP-binding band, Ponatinib binds with hydrogen Bond and π-π bond (color) interactions with MEKK3 kinase domain binding ( figure 1 , A, B, C).

Embodiment 2

[0113] Example 2, Ponatinib inhibits the activity of MEKK3 signaling pathway in the CCM gene deletion cell model

[0114]Loss of CCM genes in endothelial cells causes upregulation of MEKK3 signaling. In order to demonstrate whether Ponatinib can correct CCM lesions by inhibiting abnormal MEKK3 activity, the inventors constructed a human umbilical vein endothelial cell system with siRNA knockout of the CCM1 (siRNA) gene, and administered different doses of Ponatinib. The obtained results showed that CCM1 gene deletion increased the expression level of MEKK3 downstream target genes. In cells treated with control siRNA, Ponatinib did not affect the expression of KLF2, eNOS, and ADAMTS1; while compared with the control group, high doses of Ponatinib decreased the expression of ADAMTS4 ( figure 2 A~D). More importantly, Ponatinib treatment group can reduce the high expression of these genes in human umbilical vein endothelial cells, so that it can reach the same expression level...

Embodiment 3

[0116] Example 3, Ponatinib inhibits the formation and expansion of CCM aberration in the disease model of CCM1 gene deletion

[0117] In vitro experiments have confirmed that Ponatinib can correct abnormal signaling changes in CCM1-deficient endothelial cells. In order to confirm whether Ponatinib can alleviate CCM lesions in an animal model of CCM1 gene deletion, the inventors specifically induced the knockout of the endothelial cell CCM1 gene in an animal model (Cdh5-CreERT2; Ccm1fl / fl, marked as Ccm1 iECKO Mice) were given Ponatinib (10mg / kg) by intragastric administration ( image 3 A). Neonatal mice were induced with 4-hydroxytamoxifen (4-HT) to produce a CCM1 deletion disease model on the first day after birth, and tiny CCM lesions began to appear on the 6th day after birth, and on the 13th day, through Micro- Ccm1 can be seen on CT iECKO Mice with multiple vascular malformations ( image 3 B-D).

[0118] When the inventors in the newborn Ccm1 iECKO Ponatinib admi...

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Abstract

The invention relates to a drug for preventing and treating cerebral cavernous malformation (CCM). The invention discloses a drug which inhibits molecular passages of the CCM to further inhibit occurrence and growth of CCM focuses, and the drug is Ponatinib and also comprises analogues or derivatives of Ponatinib.

Description

technical field [0001] The invention belongs to the field of biomedicine, and more specifically, the invention relates to a medicine for preventing and treating cerebral cavernous vascular malformation. Background technique [0002] Cavernous malformation (CCM) is a common intracranial vascular lesion, which is often considered to have a high bleeding rate and is likely to cause clinical symptoms. Patients often present with focal neurological deficits such as seizures and hemorrhage. More patients present with epilepsy, and its clinical presentation is specific according to location. There is no gender difference in the incidence of cavernous malformations, with an average age of 30 to 40 years. With the development of neuroimaging, especially the clinical application of high-field-strength MRI, more and more patients are accurately diagnosed, and early diagnosis can improve the therapeutic effect. [0003] At present, cerebral cavernous vascular malformation is generall...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/5025A61P9/00A61P27/02
CPCA61K31/5025A61P9/00A61P27/02
Inventor 郑祥建
Owner TIANJIN MEDICAL UNIV
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