 |
 |
Scientific Report 2007
Scripps Florida
Molecular Therapeutics
Inhibition of Jun N-Terminal Kinase 2/3 for the Treatment of Parkinson's Disease
P. LoGrasso, M. Cameron, W. Chen, D. Duckett, J. Habel, R. Jiang, T. Kamenecka,
S. Khan, L. Lin, Y.-Y. Ling, M. Lopez, C. Ruiz, Y. Shin, L. Smith, X. Song, T. Vojkovsky,
D. Zadory
Apoptosis,
or programmed cell death, plays a vital role in the normal development of the nervous
system and is also thought to contribute to the aberrant neuronal cell death that
characterizes many neurodegenerative diseases. Therefore, blocking neuronal apoptosis
could be an approach for treating neurodegenerative diseases. A major pathway implicated
in neuronal cell death and survival is the MAP kinase pathway, which controls cell
proliferation and cell death in response to many extracellular stimuli. Recent studies
have linked Jun N-terminal kinase (JNK) activity with the cell death associated
with Parkinson's disease and Alzheimer's disease.
JNK is linked
to many of the hallmark pathophysiologic components of Parkinson's disease,
such as oxidative stress, programmed cell death, and microglial activation. Many
pieces of evidence support JNK as a target for treatment of the pathologic changes
that underlie Parkinson's disease. One attractive feature of JNK3 as a selective
drug target is that this kinase is almost exclusively expressed in the brain; levels
expressed in the kidney and testis are extremely low. In contrast, JNK1 and JNK2
are ubiquitously expressed. Despite the ubiquitous expression of JNK2, we are developing
a therapy to prevent degeneration of dopaminergic neurons and halt the progression
of Parkinson's disease by targeting JNK2/3.
Our strategy
for inhibition JNK2/3 is based on the results of experiments with mice in which
the gene for JNK3 or JNK2 was deleted and mice in which the genes for both JNK2
and JNK3 or both JNK1 and JNK2 were deleted. In contrast to mice lacking the gene
for JNK1 alone, which had defective T-cell differentiation, mice lacking the gene
for JNK2 alone had normal T- and B-cell development and normal T-cell proliferation.
Moreover, mice lacking the gene for JNK2 alone and mice lacking the gene for JNK3
alone were protected against the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP), a compound used to induce parkinsonian signs in animal models of Parkinson's
disease, whereas both wild-type and mice lacking the gene for JNK1 were not. In
other research, compared with wild-type mice, mice lacking the genes for both JNK2
and JNK3 were dramatically protected against acute MPTP-induced injury of the nigrostriatal
pathway. This protective effect resulted in a 3-fold increase in the number of neurons
positive for tyrosine hydroxylase, an indication of the increase in survival of
dopaminergic neurons.
On the basis
of these in vitro and in vivo data, we are synthesizing potent, selective JNK 2/3
inhibitors that are efficacious in MPTP animal models of Parkinson's disease.
We have established homogenous time-resolved fluorescence biochemical assays for
JNK3 and counterscreens for JNK1 and p38. We have generated more than 500 compounds
from 3 different structural classes; many of the compounds are inhibitory for JNK3
in nanomolar concentrations. Some of the compounds have a cellular potency of 40–60
nM and in vitro efficacy in promoting primary survival of dopaminergic neurons.
We have tested compounds in vivo in rats and mice for drug metabolism and pharmacokinetic
properties. Many of the JNK3 inhibitors have had good oral absorption, good brain
penetration, and good pharmacokinetic properties that enable efficacy studies.
We have also
developed an in vivo target modulation assay to monitor inhibition of c-Jun phosphorylation
and an in vivo efficacy model with MPTP to create lesions in the substantia nigra.
Moreover, we have solved the crystal structure of 10 complexes of JNK3 with inhibitor
at approximately 2.2-Å resolution. This information is being used in structure-based
drug design to help guide medicinal chemistry studies and optimize compounds for
potency, selectivity, brain penetration, oral absorption, half-life, clearance,
and efficacy.
Publications
Feng,
Y., Cameron, M.D., Frackowiak, B., Griffin, E., Lin, L., Ruiz, C., Schröter,
T., LoGrasso, P. Structure-activity
relationships and drug metabolism and pharmacokinetic properties for indazole piperazine
and indazole piperidine inhibitors of ROCK-II. Bioorg. Med. Chem. Lett. 17:2355,
2007.
Rech,
J.C., Yato, M., Duckett, D., Ember, B., LoGrasso, P.V., Bergman, R.G., Ellman, J.A.
Synthesis of potent bicyclic bisarylimidazole c-Jun N-terminal kinase inhibitors
by catalytic C-H bond activation. J. Am Chem Soc. 129:490, 2007.
|
|
