MAPK-pathway-mammalian

 

In the last post, we talked about the human protein map under development in Sweden. Here, we will proceed on this theme, but with a different kind of map, namely JNK-MAP Kinases or simply MAP Kinase. MAP Kinases are an important kind of cell signaling receptor. They are grouped off with separate identitites in order to classify for their different biological functions such as with mating and metabolism. Once stimulated, they relay messages downstream activating other kinases and gene-regulatory proteins. Within minutes of becoming activated, transcription begins on the immediate early genes, aptly named for their boundless and timeless proliferation, known to function even in the presence of strong drugs that can experimentally shutdown protein synthesis [Molecular Biology of the Cell]. Since some of these genes code for the activity of other gene-regulatory proteins, it holds to a wider premise that life itself really just requires two inputs: (1) protein synthesis, and (2) time.

c-Jun-NH2-terminal kinases (JNK), in particular, help direct cellular activities in response to cellular oxidative stress and other stimuli including cytokines, hormones, and peptides. Deviation from this strictly controlled process often leads to many human diseases including Alzheimer’s disease, Parkinson’s disease, ALS, and various forms of cancer [Molecular Basis of Disease].

That’s why the news out of The Scripps Research Institute’s (TSRI) Florida campus came as a surprise this week when they announced they have identified certain drug candidates which can positively identify and target the signaling pathways implicated in the destruction of brain matter in Parkinson’s disease.

According to two studies, “Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives” and "Structural Basis and Biological Consequences for JNK2/3 Isoform Selective Aminopyrazoles"), published in the Journal of Medicinal Chemistry and Scientific Reports, respectively, report that their drug candidates work by inhibiting each of the JNK kinases (JNK1, JNK2, JNK3) mitochondrial enzymes, and that it’s possible to develop highly precise medical practices that can protect the battery life on your cell’s mitochondria.

"These are the first isoform selective JNK 2/3 inhibitors that can penetrate the brain and the first shown to be active in functional cell-based tests that measure mitochondrial dysfunction," said Philip LoGrasso, Ph.D., a TSRI professor who led both studies. "In terms of their potential use as therapeutics, they've been optimized in every way but one: their oral bioavailability. That's what we're working on now."

The researchers extrapolated this idea further in their Journal of Medicinal Chemistry article stated that with proper dosing, isoform selectivity, and pharmacological properties, the JNK 2/3 inhibitors showed a higher selectivity, and perhaps advantage over JNK1 and p38a, in its ability to protect mitochondrial degradation, promote good drug metabolism, while adding pharmacokinetic value, with minimal reported cytotoxic effects.

HaJeung Park, Ph.D., director of Scripps Florida's X-ray Crystallography Core Facility and the first author of the Scientific Reports study said in a news release stating, "Some of these compounds had a level of selectivity that ranged as high as 20,000-fold against competing targets and were extremely effective against oxidative stress and mitochondrial dysfunction--both potent cell killers."

Astonishingly, these scientists found that a single amino acid within JNK3 (L144) was primarily responsible for JNK3’s high level of specificity. This kind of painstaking accuracy can help doctor’s to limit some of the unwanted and potential damaging side effects of a drug.

Together these new studies bolster hope that medical intervention for Parkinson’s disease is possible and that it can soon one day prevent the gradual degeneration of a person’s brain. Other recent studies corroborate with TSRI findings, but go further to suggest that JNK inhibitors can also help with Alzheimer’s disease.

Dr. LoGrasso and his colleagues believe their JNK3 drug candidates may hold, still, a wider promise to treat, and eventually beat, ALS (Lou Gehrig’s disease).

 

Further Reading

 

SOURCES/REFERENCE MATERIAL

Image Credit: Wikipedia. Creative Commons Attributable License.

“Scripps Florida Scientists Establish that Drug Candidates Can Block Pathway Associated with Cell Death in Parkinson’s Disease.“ The Scripps Research Institute News Release. January 27, 2015. [February 2, 2015]. <http://www.scripps.edu/news/press/2015/20150127lograsso.html>

Design and Synthesis of Highly Potent and Isoform Selective JNK3 Inhibitors: SAR Studies on Aminopyrazole Derivatives. Ke Zheng, Sarah Iqbal, Pamela Hernandez, HaJeung Park, Philip V. LoGrasso, and Yangbo Feng. Journal of Medicinal Chemistry. 2014. 57 (23), 10013-10030. <http://pubs.acs.org/doi/abs/10.1021/jm501256y>

Structural Basis and Biological Consequences for JNK2/3 Isoform Selective Aminopyrazoles. HaJeung Park, Sarah Iqbal, Pamela Hernandez, Rudy MOra, Ke Zheng, Yangbo Feng, and Philip LoGrasso. Scientific Reports. January 27, 2015. 8047 (5). <http://www.nature.com/srep/2015/150127/srep08047/full/srep08047.html>

Molecular Biology of the Cell. by John Wilson, Tim Hunt; Garland Science, 4th edition, 2002. Pages 878-879.

EK Kim, EJ Choi, Pathological roles of MAPK signaling pathways in human diseases. Molecular Basis of Disease. [1802] 4. April 2010. Pages 396-405. doi:10.1016/j.bbadis.2009.12.009