主催: The Japanese Pharmacological Society, The Japanese Society of Clinical Pharmacology
会議名: WCP2018 (18th World Congress of Basic and Clinical Pharmacology)
開催地: Kyoto
開催日: 2018/07/01 - 2018/07/06
Abstract
Background
Autophagic dysfunctions are referred as a pathologic mechanism for neurodegenerative diseases such as Alzheimer disease. Some studies indicated that beclin-1 a protein with a key role in autophagy was decreased in the brain of AD patients. Moreover inhibition of ErbB2 not only upregulated expression of beclin-1 but also attenuated amyloid-b production suggesting that ErbB2 is a novel target for AD.
Methods
In this study a type of new quinazoline derivatives as ErbB2 inhibitors was synthesized based on the modification of the lead CL-387785 for improving selectivity and potency. Modulation of Ab autophagy by measuring the g-secretase activity and the change of amount of Ab through ErbB2 inhibition in cell-based assays was carried out to explore the potential therapies for AD.
Results
The synthetic compounds modified with biarylamino groups at 4-position gave detrimental effects on the autophagic clearance of Ab and AICD. Additional methoxy group at 7-position but keeping halogenated anilinyl moiety at 4-position furnished selective Inhibition of ErbB2 significantly and alleviated the production of C99 and AICD in HEK293 Cells. Whether inhibition of ErbB2 alleviates the production of Ab and renders cognitive improvement will be carried out in transgenic mice in due course.
Conclusions
Based on the mechanism of actions of certain tyrosine kinase inhibitory activities on the autophagic modulation Ab we came up with some new derivatives that significantly and selectively decreased the production of g-secretase mediated Ab.
Key words: Alzheimer disease; amyloid-b; autophagy
