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Wednesday, December 10, 2014 10:08:25 PM
Other projects, coupled with the explosive growth of nearly every stock I follow, has shifted my focus a bit these past few months so you'll have to forgive me.
One of the most surprising things about this compound is that it is very similar to Lanvis, yet lacks many of the adverse affects typically associated with this cancer drug -often used for psoriasis.
GSK
http://en.wikipedia.org/wiki/Tioguanine
As a plus, it shares some antimetabolite traits with Methotrexate. We kinda know who the winner is already though ;)
http://en.wikipedia.org/wiki/Methotrexate
For those of you who want to get a closer look at G1P3 AKA IFI6
http://www.wikigenes.org/e/gene/e/2537.html
The only blemish in the drugs development, as some of TOB's research pointed out, is that the drugs efficacy was demonstrated in HIV/AIDS patients. As some of you know, SCID mice were used in the preclinical zenograft models. The fact that SCID mice are a great model for HIV/AIDS pathology, makes it hard to say difinitively that the drug works in humans not infected with HIV/AIDS.
I hope investors notice that this drug isn't like the psoriasis drugs of old. Even if the SCID issue causes less of an effect on humans and this isn't really a big 'IF'. I still think an efficacious dose can be found with some alterations.
After today's price movement, I feel most don't understand it's value.
I left off on some promising discoveries, but I'm not very well versed in genetics so that's about where I tapped out.
G1P3 (6-16)
"It is possible that the context of the combined motifs has a profound effect on their function or that small variations in the sequencescan modulate the response(interferon inducible) or even abolish it, as is the case for protein binding for the example of the single base change shown in Figure 6B. While everything is consistent with a major role for the 14 nucleotide sequence, flanking sequences and additional factors may well play an important role in modulating the response."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC454218/pdf/emboj00138-0087.pdf
Long non-coding RNAs in aging and disease
Overexpression of PRINS is associated with psoriasis susceptibility, with PRINS expression being elevated in the uninvolved epidermis of psoriatic patients compared with both psoriatic lesions and healthy epidermis (Sonkoly 2005).
http://en.wikipedia.org/wiki/Long_non-coding_RNA
Guanosine is required for an RNA splicing reaction in mRNA, when a "self-splicing" intron removes itself from the mRNA message by cutting at both ends, re-ligating, and leaving just the exons on either side to be translated into protein.
Research path
![](http://patentimages.storage.googleapis.com/US20140200229A1/US20140200229A1-20140717-C00010.png)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829857/
http://www.nature.com/gene/journal/v5/n2/full/6364046a.html
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565259/
https://www.deepdyve.com/lp/wiley/the-anti-apoptotic-protein-g1p3-is-overexpressed-in-psoriasis-and-PZNT0nM2mO/1
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390387/
https://www.deepdyve.com/lp/elsevier/new-developments-in-the-enantioselective-synthesis-of-cyclopentyl-lNHSwSJjE1/2
http://www.pharmgkb.org/pathway/PA166104634#tabview=tab0&subtab=
http://en.wikipedia.org/wiki/Guanosine_triphosphate
http://en.wikipedia.org/wiki/Signal_transduction
http://en.wikipedia.org/wiki/G_protein
http://en.wikipedia.org/wiki/Ras_subfamily
http://en.wikipedia.org/wiki/GTPase
http://en.wikipedia.org/wiki/CpG_site
http://www.nature.com/jid/journal/v132/n3-1/full/jid2011348a.html
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262011/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC187879/
http://www.jbc.org/content/266/3/1754.full.pdf
http://en.wikipedia.org/wiki/Tioguanine
http://www.ncbi.nlm.nih.gov/gene/2537
http://www.ncbi.nlm.nih.gov/gene/2633
https://www.wikigenes.org/e/gene/e/2537.html
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC365501/
http://en.wikipedia.org/wiki/GBP1
Nucleophosmin "Our data indicate that PRINS does not act alone, but forms a complex with the NPM protein and contributes to its stress-related intracellular trafficking."
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565259/
LncRNA & Epigenetics
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177375/
STAT
IFI6 is also known as G1P3
![](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829857/bin/pone.0079253.g008.jpg)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC514583/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829857/
PP-increased DEMs with genes biased towards hypo-methylation i.e.STAT3-30 and WNT5A-48
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3829857/
"Taken collectively, it seems plausible that the cytokine/growth factor profile associated with psoriasis converges on Stat3 signaling in epidermal keratinocytes."
http://www.nature.com/jid/journal/v131/n1/full/jid2010255a.html
Guanosine Inhibits CD40 Receptor Expression and Function Induced by Cytokines and Beta Amyloid in Mouse Microglia Cells
http://www.jimmunol.org/content/178/2/720.full
http://brain.oxfordjournals.org/content/131/1/90
Patent mentions the low levels of cAMP in Psoriasis tissue
https://www.google.com/patents/US20140200229?dq=prurisol&hl=en&sa=X&ei=BzpZVM3iEMT4igLe7oGwBQ&ved=0CCYQ6AEwAQ
cGMP-Dependent Protein Kinase Inhibitors in Health and Disease
"Kinases are enzymes that transmit phosphate groups from a donor, usually a nucleoside
triphosphate (e.g., ATP), to specific substrates. This phosphorylation results in a functional change of
the substrate protein. A large group of kinases are protein kinases, which catalyze the transfer to a special amino acid in most cases with a free hydroxyl group."
cGMP acts as a second messenger much like cAMP. cGMP is a Cyclic nucleotide derived from guanosine triphosphate(Carbovir is Guanosine analogue)
http://en.wikipedia.org/wiki/Cyclic_guanosine_monophosphate
http://www.jbc.org/content/276/8/5967.full
http://link.springer.com/article/10.1007/s00210-011-0662-6/fulltext.html
2-aminopurine inhibited induction of mRNAs 6-16
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC365501/pdf/molcellb00070-0327.pdf
http://en.wikipedia.org/wiki/IFI6
12R-lipoxygenase
http://en.wikipedia.org/wiki/ALOX12B
https://www.wikigenes.org/e/gene/e/242.html
http://atlasgeneticsoncology.org//Genes/GC_ALOX12B.html
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC22619/
Why Tris-acetate?
http://en.wikipedia.org/wiki/Tris
http://www.sciencedirect.com/science/article/pii/0049384886902665
http://books.google.com/books?id=nMm2WfrH3fIC&pg=PR5&lpg=PR5&dq=nucleosides+sulfate+acetate&source=bl&ots=GPq4DNJ8Og&sig=pv_h5VvVIdy28Uq72GyTwkVkZ3s&hl=en&sa=X&ei=sItdVJCjL9CxogTLr4AI&ved=0CC4Q6AEwAw#v=onepage&q=nucleosides%20sulfate%20acetate&f=false
Guanylate cyclase (Guanyl cyclase; Guanylyl cyclase)
http://www.lookfordiagnosis.com/mesh_info.php?term=guanylate+cyclase&lang=4
http://www.researchgate.net/publication/26683958_Cross_talk_between_receptor_guanylyl_cyclase_C_and_c-src_tyrosine_kinase_regulates_colon_cancer_cell_cytostasis
AE's
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3272328/
http://www.sciencedirect.com/science/article/pii/S0960894X10014423
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785446/
PRINS
http://www.jbc.org/content/280/25/24159.long
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3565259/
"PRINS is strongly expressed in the uninvolved psoriatic epidermis and its expression is substantially down regulated in the hyper proliferative involved epidermis". This coupled with the use of SCID mice has the potential to skew the data. SCID mice are effective models for HIV/AIDS driven immunosuppression, so previous success in studies with Psoriasis and HIV maybe exclusive to this disease.
Menon could overlooked this in his study, but it's not really clear what methods were used to show PRINS reduction. He's much smarter than I, so I figure he tested the uninvolved tissue.
Dr. Reddy's Psoriasis related ventures.
http://www.firstpost.com/india/dr-reddys-9-new-drugs-clinical-stage-reveals-sec-filing-1594359.html
http://promiuspharma.com/products.html
http://clinicaltrials.gov/ct2/show/study/NCT01947491
http://clinicaltrials.gov/show/NCT01496352
There are some dead ends in there, but from what I remember most of it is plausible. I whish I had more time to put it altogether concisely for you guys.
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