Has anyone looked into this issue?
@KarlT brings up this issue in this posting:
Not many mentions of this drug. Would be hard to use, but some papers indicate it is a selective mtorc1 inhibitor without mtorc2 inhibition.
Has anyone looked in depth into the issue as to whether Temsirolimus might be a drug that avoids the mTORC2 inhibition that we see eventually with rapamycin and everolimus?
Here is what I’ve found so far… while its classified (like all rapalogs) as strictly an mTORC1 inhibitor, we all know that there is some sort of feedback mechanism with prolonged, high-dose rapamycin and everolimus use , that eventually results in mTORC2 suppression.
The question is, does Termsirolimus have that same problem of eventual mTORC2 inhibition with prolonged or high dosing?
Rapamycin (also named sirolimus, Wyeth) and other rapalogues including temsirolimus (CCI-779, Wyeth), everolimus (RAD001, Novartis Pharmaceutical), and deforolimus (AP23573, Ariad Pharmaceutical) are macrocyclic lactones acting as anticancer agents that target mTOR in several human cancers in vitro and in vivo. The main differences between rapalogues lie in changes in chemical properties in terms of drug solubility and metabolism. As a result, temsirolimus and deforolimus are water soluble and may be administered intravenously, whereas rapamycin and everolimus display low solubility, and therefore are available only for oral formulations. Rapalogues bind very similarly to the intracellular immunophilin-, FK506, binding protein-12 (FKBP12) and selectively inhibit mTORC1, but have no direct effects on mTORC2. Potency to inhibit mTORC1 seems to be identical across rapalogues. The inhibitory effects of rapalogues on mTORC1 do not seem to affect the kinase activity of mTOR. Although limited experiments have been carried out to benchmark and address cross-resistance between rapalogues, similarities in terms of chemical structures, mechanisms of action, affinity for the target, and overall spectrum of activity in laboratory experiments strongly suggest that currently developed rapalogues are similar in many ways, the main differences belonging to pharmacokinetic properties rather than to antitumor potency.