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Page 10 of 25 Kondapuram et al. J Cancer Metastasis Treat 2019;5:32 I http://dx.doi.org/10.20517/2394-4722.2018.105

Figure 7. Pan-mTORC inhibitors

Pan-mTORC inhibitors
Activation of mTORC1 and mTORC2 is important in many cancers. Compounds with ATP competitive
mechanism inhibiting both mTORC1 and mTORC2 offer better alternative to rapalogs. Torin 1 [Figure 7], is
a commercially available autophagy inhibitor that is selective and highly potent ATP-competitive inhibitor
of both mTORC1 and mTORC2. Torin 1 shows more efficacy towards blocking the phosphorylation of
mTORC1 and mTORC2, when compared with rapamycin a well-known classical mTOR allosteric inhibitor.
In vitro kinase assay reveals that Torin 1 has an IC of 3 nmol/L, 3 µmol/L, 1.8 µmol/L and 1 µmol/L for
50
mTOR, hVps34, PI3K-α and DNA-PK, respectively. The results show that Torin 1 is more selective for
mTOR inhibition over other kinases . Second generation ATP-competitive inhibitor, Torin 2 is a potent
[60]
and selective inhibitor of mTOR with better pharmacokinetics profile to overcome the limitations of Torin
1. In vitro studies revealed that Torin 2 reduced cell proliferation in several cancer cell lines and exhibited
combinatorial response with AZD6244, an inhibitor of MEK kinase in the molar ratio of 1:50. Torin 2 shows
inhibition of several PI3KK family proteins including mTOR, ATM, ATR and DNA-PKs with an IC value
50
[66]
of less than 10 nmol/L ; whereas, Torin 1 inhibits only mTOR, ATR and DNA-PK. Further, effects of Torin
2 in autophagosome formation were examined and found to induce autophagy .
[66]
AZD8055 is another novel ATP-competitive inhibitor of mTOR kinase (IC of 0.8 nmol/L) that shows
50
[67]
approximately 1000-fold selectivity against other kinases . Remarkably, in xenografts studies, AZD8055
shows substantial growth inhibition and suggests that AZD8055 can be a potent therapeutic drug in many
[67]
human cancer treatments . AZD8055 treated acute myeloid leukemia cells have shown significant decrease
in cell cycle progression and cell proliferation in blast phase. More interestingly, AZD8055 treatment results
[68]
in decreased growth of leukemic progenitors but not normal immature CD34+ cells . Another independent
study also revealed that AZD8055 treated chronic lymphoid leukemia (CLL) cells show significant reduction
in CLL cell proliferation and increase in apoptosis. Currently, this inhibitor is in phase 1 clinical trials.

WYE-354, another heterocyclic compound is a powerful dual ATP-competitive kinase inhibitor that
selectively blocks mTORC1/2 activity with an IC value of 4.3 nmol/L. Although it displays a weak inhibition
50
of PI3Kα, it has no inhibitory effect on other proteins/kinases. In vitro analysis revealed that WYE-354
potently blocks several cancer cell proliferation including LNCap, A498, MDA-MB-231, MDA-MB-361,
MDA-MB-468 and HCT116 cell lines. Mechanistically, WYE-354 arrests cell cycle at G1 phase and induces