1 research outputs found
Benzodiazepinone Derivatives Protect against Endoplasmic Reticulum Stress-Mediated Cell Death in Human Neuronal Cell Lines
Endoplasmic
reticulum (ER) stress causes neuronal dysfunction followed
by cell death and is recognized as a feature of many neurodegenerative
diseases. Using a phenotypic screen, we recently identified benzodiazepinone
derivatives that reduce ER stress-mediated apoptosis in a rat neuronal
progenitor cell line (CSM14.1). Herein we describe how structure–activity
relationship (SAR) studies around these screening hits led to compounds
that display robust cytoprotective activity against thapsigargin-induced
ER stress in SH-SY5Y and H4 human neuronal cell lines. We demonstrate
that the most potent of these derivatives, compound <b>4hh</b>, inhibits the activation of p38 MAP kinase (p38) and c-Jun N-terminal
kinase (JNK), protein kinases that are downstream signal effectors
of the unfolded protein response (UPR). Compound <b>4hh</b> specifically
protects against thapsigargin-induced cell death and displays no protection
against other insults known to induce cellular stress or activate
p38. However, compound <b>4hh</b> provides moderate inhibition
of p38 activity stimulated by compounds that disrupt calcium homeostasis.
Our data indicate that probe compound <b>4hh</b> is a valuable
small molecule tool that can be used to investigate the effects of
ER stress on human neurons. This approach may provide the basis for
the future development of therapeutics for the treatment of neurodegenerative
diseases