thought id save you the effort - not a boarder hoarder, share and share alike.
hope you're over your Gamecocks --- have to say I was pulling for Clemson. quite the un-Saban thing to do to pull that onside kick. changed everything.
//
"Human tumor-derived p53 mutants: a growing family of oncoproteins" ... new studies posted to the series, inc overview of MDM/X inhibitors, one on APR-246
The overview of MDM/X an esp good read, spot-on on topic. Interesting Kevetrin yet again is overlooked: why?... Bad DD? APR-246 bias? Pink sheet stigma? I pinged the researcher listed highlighting this oversight (haven't heard back). The article on APR-246 also misstates it's "the only mutant p53-targeting compound in clinical development" (huh). I can see why APR-246 researchers might conveniently fail to mention Kevetrin (direct competitor). In past studies they put out earlier in 2015, there was the same, ahem, oversight... guess that's why they have conflict of interest disclosures.
Anyway, the MDM/X commentary reinforces how Kevetrin's nongenotoxic profile really sets it apart from those more toxic p53 agents that have gone before, how such drugs like K best positioned as combo agents. Also info in tables at end -- p53 by cancer type, current MDM2/X trials (most stuck in Ph I, if that, if reporting results of closed trials) -- good stuff.
All in all, v exciting to think Kevetrin might soon be the p53 leader -- ahead of Roche, Novartis, Amgen, etc., agents -- with multiple ph IIs, whereas others have stalled, met with too much toxicities. I keep going back to the U of Col p53 researcher/guru who said the first p53/mdm2 inhibitor approved (he didn't think APR-246 was it, btw, not impressed w PRIMA-1 MOA) was going to change the world.
Some related reads below.
"The p53 Circuit Board" (2012)
(read the Final Remarks section, pg 12 of the PDF... "We ask the reader to picture the following scenario, not too far into the future... [enter Kevetrin?]... Within days, the tumor regresses and the reader is considered cancer free. Science fiction or rational optimism?"
http://espinosalab.org/media/2012SullivanetalPUBLISHED.pdf
"Cancer's Dead End: There is a way to restore p53's tumor-suppressing prowess" (Fall 2012) ("The future is not in isolated drugs, but rather in combinations of drugs."
https://www.hhmi.org/sites/default/files/espinosa_p53.pdf
Of course, we still need to see more data (that Ph I Dana Farber readout), but Kevetrin plugging along toward becoming the long-awaited, much-anticipated first p53-activating therapy. What you, ferrell90, outlined so well in your post--no guarantee, but its promise turning more and more into a reality as additional FDA designations granted (Breakthrough Therapy would be huge), more trials lined up.
In the meantime, Brilacidin setting up as a nice placeholder. And Prurisol, the dark horse that just might break the tape first.
Build the Pipeline, as Leo is doing, and Big Pharma eventually will come knocking.
Have sent links to CTIX.
http://journal.frontiersin.org/researchtopic/...coproteins
//
FULL
Targeting of mutant p53 and the cellular redox balance by APR-246 as a strategy for efficient cancer therapy
http://journal.frontiersin.org/article/10.338....00021/pdf
Vladimir J.N. Bykov, Qiang Zhang, Meiqiongzi Zhang, Sophia Ceder, Lars Abrahmsen and Klas G Wiman
TP53 is the most frequently mutated gene in cancer. The p53 protein activates transcription of genes that promote cell cycle arrest or apoptosis, or regulate cell metabolism and other processes . Missense mutations in TP53 abolish specific DNA ...
Accepted on 19 January 2016
Front. Oncol. doi: 10.3389/fonc.2016.00021
FULL
Mutant p53 drives cancer by subverting multiple tumour suppression pathways
http://journal.frontiersin.org/article/10.338....00012/pdf
Sue Haupt, Dinesh Raghu and Ygal Haupt
The tumour suppressor p53 normally acts as a brake to halt damaged cells from perpetrating their genetic errors into future generations. If p53 is disrupted by mutation, it may not only lose these corrective powers, but counter-productively acquire ...
Accepted on 12 January 2016
Front. Oncol. doi: 10.3389/fonc.2016.00012
FULL
Clinical overview of MDM2/X targeted therapies
http://journal.frontiersin.org/article/10.338....00007/pdf
Andrew Burgess, Kee Ming Chia, Sue Haupt, David Thomas, Ygal Haupt and Elgene Lim
MDM2 and MDMX are the primary negative regulators of p53, which under normal conditions, maintain low intracellular levels of p53 by targeting it to the proteasome for rapid degradation, and inhibiting its transcriptional activity. Both MDM2 and MDMX ...
Accepted on 11 January 2016
Front. Oncol. doi: 10.3389/fonc.2016.00007
hope you're over your Gamecocks --- have to say I was pulling for Clemson. quite the un-Saban thing to do to pull that onside kick. changed everything.
//
"Human tumor-derived p53 mutants: a growing family of oncoproteins" ... new studies posted to the series, inc overview of MDM/X inhibitors, one on APR-246
The overview of MDM/X an esp good read, spot-on on topic. Interesting Kevetrin yet again is overlooked: why?... Bad DD? APR-246 bias? Pink sheet stigma? I pinged the researcher listed highlighting this oversight (haven't heard back). The article on APR-246 also misstates it's "the only mutant p53-targeting compound in clinical development" (huh). I can see why APR-246 researchers might conveniently fail to mention Kevetrin (direct competitor). In past studies they put out earlier in 2015, there was the same, ahem, oversight... guess that's why they have conflict of interest disclosures.
Anyway, the MDM/X commentary reinforces how Kevetrin's nongenotoxic profile really sets it apart from those more toxic p53 agents that have gone before, how such drugs like K best positioned as combo agents. Also info in tables at end -- p53 by cancer type, current MDM2/X trials (most stuck in Ph I, if that, if reporting results of closed trials) -- good stuff.
All in all, v exciting to think Kevetrin might soon be the p53 leader -- ahead of Roche, Novartis, Amgen, etc., agents -- with multiple ph IIs, whereas others have stalled, met with too much toxicities. I keep going back to the U of Col p53 researcher/guru who said the first p53/mdm2 inhibitor approved (he didn't think APR-246 was it, btw, not impressed w PRIMA-1 MOA) was going to change the world.
Some related reads below.
"The p53 Circuit Board" (2012)
(read the Final Remarks section, pg 12 of the PDF... "We ask the reader to picture the following scenario, not too far into the future... [enter Kevetrin?]... Within days, the tumor regresses and the reader is considered cancer free. Science fiction or rational optimism?"
http://espinosalab.org/media/2012SullivanetalPUBLISHED.pdf
"Cancer's Dead End: There is a way to restore p53's tumor-suppressing prowess" (Fall 2012) ("The future is not in isolated drugs, but rather in combinations of drugs."
https://www.hhmi.org/sites/default/files/espinosa_p53.pdf
Of course, we still need to see more data (that Ph I Dana Farber readout), but Kevetrin plugging along toward becoming the long-awaited, much-anticipated first p53-activating therapy. What you, ferrell90, outlined so well in your post--no guarantee, but its promise turning more and more into a reality as additional FDA designations granted (Breakthrough Therapy would be huge), more trials lined up.
In the meantime, Brilacidin setting up as a nice placeholder. And Prurisol, the dark horse that just might break the tape first.
Build the Pipeline, as Leo is doing, and Big Pharma eventually will come knocking.
Have sent links to CTIX.
http://journal.frontiersin.org/researchtopic/...coproteins
//
FULL
Targeting of mutant p53 and the cellular redox balance by APR-246 as a strategy for efficient cancer therapy
http://journal.frontiersin.org/article/10.338....00021/pdf
Vladimir J.N. Bykov, Qiang Zhang, Meiqiongzi Zhang, Sophia Ceder, Lars Abrahmsen and Klas G Wiman
TP53 is the most frequently mutated gene in cancer. The p53 protein activates transcription of genes that promote cell cycle arrest or apoptosis, or regulate cell metabolism and other processes . Missense mutations in TP53 abolish specific DNA ...
Accepted on 19 January 2016
Front. Oncol. doi: 10.3389/fonc.2016.00021
FULL
Mutant p53 drives cancer by subverting multiple tumour suppression pathways
http://journal.frontiersin.org/article/10.338....00012/pdf
Sue Haupt, Dinesh Raghu and Ygal Haupt
The tumour suppressor p53 normally acts as a brake to halt damaged cells from perpetrating their genetic errors into future generations. If p53 is disrupted by mutation, it may not only lose these corrective powers, but counter-productively acquire ...
Accepted on 12 January 2016
Front. Oncol. doi: 10.3389/fonc.2016.00012
FULL
Clinical overview of MDM2/X targeted therapies
http://journal.frontiersin.org/article/10.338....00007/pdf
Andrew Burgess, Kee Ming Chia, Sue Haupt, David Thomas, Ygal Haupt and Elgene Lim
MDM2 and MDMX are the primary negative regulators of p53, which under normal conditions, maintain low intracellular levels of p53 by targeting it to the proteasome for rapid degradation, and inhibiting its transcriptional activity. Both MDM2 and MDMX ...
Accepted on 11 January 2016
Front. Oncol. doi: 10.3389/fonc.2016.00007
