YF2, A Novel HAT Activator Against Alzheimers Disease Background - - - PowerPoint PPT Presentation

▶

Dec 29, 2022 1.01k likes •1.13k views

Elisa Calcagno, Ph.D. 14 th Annual Drug Discovery For Neurodegeneration Workshop: Translating Research Into Novel Drug Targets. April 27-May 11, 2020 YF2, A Novel HAT Activator Against Alzheimers Disease Background - Memory is modulated by

SLIDE 1

YF2, A Novel HAT Activator Against Alzheimer’s Disease

Elisa Calcagno, Ph.D.

14th Annual Drug Discovery For Neurodegeneration Workshop: Translating Research Into Novel Drug Targets. April 27-May 11, 2020

SLIDE 2

Background

Memory is modulated by epigenetics

through regulation of gene expression

The competing activities of histone

acetyltransferases (HATs) and histone deacetylases (HDACs) influence the post-translational acetylation status of chromatin, which regulates gene expression.

Histones acetylation causes the

chromatin structure to open making the DNA more accessible to transcription

factors. This promotes the transcription of

genes involved in memory process. Acetylation

SLIDE 3

YF2 has good pharmacodynamics and pharmacokinetics properties and is not toxic

A B C D

Acetylation syte EC50 (nM) H3K27 72.54 nM ± 0.27 H3K18 155.01 nM ± 0.32

SLIDE 4

YF2 rescues Aβ-induced defects in synaptic plasticity and memory

A B C D E F APP/PS1 mice Aβ-infused mice

SLIDE 5

YF2 rescues Tau-induced defects in synaptic plasticity and memory

A B C

SLIDE 6

Future Directions/Conclusions

▪

HAT acetylation represents a very promising strategy to ameliorate synaptic function and memory for the treatment of AD and AD-related disorders.

▪

We have designed and synthesized a library of 74 small molecules of which 2 compounds have shown improved metabolic stability.

Acknowledgments

Donald W. Landry, Ottavio Arancio, Jennifer Amengual, Shi-Xian Deng, Jole Fiorito, Elisa Zuccarello, Yuxuan Liu, Luuk De Vries, Agnieszka Staniszewski, Hong Zhang, Erica Acquarone

Activators

MEMORY LTP