RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:RE:TH2101Sorry for the nerdy stuff, but finally, MPEP (1-[2-(2-tert-butyl-5-methylphenoxy)-ethyl]-3-methylpiperidine is not interacting with sortilin, but it works to prevent the cell from expressing sortilin in the first place. So it prevent the cell from making sortilin, the result is that it not there on the membrane to bind progranulin and internalize it. So it increases the level of extracellular progranulin. So again, it deregulates the sortilin-progranulin axis involved in cancer aggressivity, which the use of significant doses of TH1902 is also likely to do, at least to some extent.
https://www.researchgate.net/figure/MPEP-decreases-SORT1-expression-and-increases-extracellular-PGRN-in-mammalian-cell-lines_fig1_258104060
jfm1330 wrote: So here I think I have the Sortina approach. Using a small molecule called MPEP (1-[2-(2-tert-butyl-5-methylphenoxy)-ethyl]-3-methylpiperidine, which they describe as a sortilin affecting compound. So clearly the idea is to deregulate the sortilin-progranulin axis. Again, TH1902 is doing that as a secondary effect. The primary goal of TH1902 is not to deregulate the sortilin-progranulin axis, it is to use sortilin to introcude docetaxel inside the cancer cells, but with a sufficient dose, it is also deregulating the sortilin-progranulin axis by forcing the endocytosis of most of the sortilin receptors. Again, the dose of TH1902 needs to be sufficient to saturate the sortilin receptors. Then the question is to know how long this deregulation would last. How long does it takes cancer cells to make new sortilin oy to recycle the one that was intenalize. But you add docetaxel into these cells at the same time. So this is pretty complicated stuff.
jfm1330 wrote: The sortilin receptor is a prerequisite for progranulin-induced CSC-like propagation
In order to identify how progranulin induced cancer stem cell propagation we investigated the role for the receptor sortilin, previously identified as one of the main receptors for progranulin [24, 25]. Silencing of sortilin using siRNA-inhibited progranulin induced increase in mammosphere formation of both MCF7 (Fig. 2a) and MDA-MB 231 cells (Additional file 1: Figure S3A). Similar results were obtained when treating cells with the recently identified sortilin affecting compound 1-[2-(2-tert-butyl-5-methylphenoxy)-ethyl]-3-methylpiperidine termed MPEP [16] (Fig. 2b and Additional file 1: Figure S3B). The small orally available sortilin inhibitor AF38469 [26] was also tested and effectively inhibited the progranulin-mediated mammosphere-forming capacity of MCF7 cells (Fig. 2c) and MDA-MB 231 cells (Additional file 1: Figure S3C) without affecting proliferation and cell viability (Additional file 3). Taken together, these results demonstrate that progranulin-induced cancer stem cell-like propagation is dependent on sortilin expression and function.