Hi Jockthegreat,
Your question is basically what’s the difference between MPL and other mTOR inhibitors , and why have the others not achieved their intended goals ?
There is now four generations of mTOR inhibitors. Rapamycin approved by the FDA the first in 1997.
It only inhibits mTOR activity, it didn’t bind with the kinase ( cell signalling in the Cancer cell).
The second generation was called Rapalogs, they were formed by replacing the hydrogen element in the Rapamycin molecule. They had better solubility and a smaller molecules, they were called Temsirolimus/Everolimus and Ridaforalimus. Efficacy in Cancer was improved marginally. They were authorised by the FDA in 2007. But, the only target seemingly for these rapalogs was renal cell carcinoma and mantle cell lymphoma. Rapalogs also didn’t cause cancer cell death. What was found that prolonged drug administration caused a negative feedback loop that resulted in promoting the P13K/ AKT( cellular replication pathway) activity which actually helped the cancer cells proliferate.
Does MPL have the same activity, the answer is No.
Along came a third generation of mTOR inhibitors that possessed inhibitory P13K/AKT activity, but are they selective enough to combat the many types of cancer. The answer is No. They still don’t “kill” the cancer cell, at best they suppress it.
Out of chance, a very smart chap called Dr Roger Aston found that not only does MPL inhibits the P13K/AKT pathway but, in addition MPL arrests the cell cycle of the cancer. It killed the cancer. He decided to explain why, under a microscope, Roger found that the cancer cells had a loss of plasma integrity. Thus allowing our bodies immune response via our killer T cells to clear other cancer cells. Generation four had begun.
So that’s it, Monepantel works in Cancer differently in MND as well as Covid 19.
Jock, your next question may be who else has our knowledge. There is three competitors MLN0128 as well as PP242 then AZD2014. Do they work yes, do they have a more limited range of targets, yes.
They are all in Phase 2 studies to my knowledge.
We have the edge.
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