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A. Verma
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Poster Display Session (ID 63)
- Event: ELCC 2017
- Type: Poster Display Session
- Track:
- Presentations: 2
- Moderators:
- Coordinates: 5/07/2017, 12:30 - 13:00, Hall 1
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41P - Development of novel 1,2,4-triazole-thiol derivatives as dual PI3K/mTOR inhibitor against the non-small cell lung cancer (NSCLC) (ID 435)
12:30 - 13:00 | Author(s): A. Verma
- Abstract
Background:
PI3K catalyzes the ATP-dependent phosphorylation of the 3'-hydroxyl group of phosphatidylinositols and plays an important role in cell growth and survival. However, most of the inhibitors in this signaling pathway have inhibitory effect against both PI3K and mammalian target of rapamycin (mTOR) kinases. It is well known that the mTOR, regulate cell proliferation, apoptosis, angiogenesis, and metabolism through both AKT-dependent and AKT-independent mechanisms. Agents targeting PI3Ks with additional mTOR kinase inhibitory have more advantageous than alone inhibition. Our efforts to identify potent and efficacious PI3K/mTOR dual inhibitors resulted in the discovery of a series of substituted 1,2,4-triazole-thiol derivatives.
Methods:
The entire set of the designed compounds were assessed on the Lipinski rule of five for drug-likeness prediction using Molinspiration and synthesized via novel synthetic procedure. The anticancer activity was evaluated against panel of three human NSCLC cell lines A549, H157 and H52 together with effect on cell cycle. The compounds were also evaluated for inhibitory activity against PI3K and mTOR via kinase inhibitory assay together with molecular docking experiments (PI3K; 3s2a.pdb) to rationalize the mechanism of action.
Results:
The compounds were developed in excellent yield and found to be significantly activity against the panel of the cell lines. The most active compound 6b showed significant inhibitory activity with IC50 of 4.56, 7.23 and 9.21 µmol/l against A549, H157 and H52, respectively, with highest activity against A549 (IC50 = 1.13 µmol/l). The compound 6b causes a significant arrest of G2/M phase and induces tumor cell apoptosis in a concentration dependent manner. In a PI3K/mTOR inhibition assay, 6b showed IC50 of 1.43±0.21 µM and 2.32±0.12 against PI3Ks and mTOR, respectively. Moreover, the docking results showed that 6b efficiently inhibit PI3Ks via channeling in ATP pocket with Ki of 436.57 nM. It showed to interact with Met804, ILE831, ILE879.
Conclusions:
In conclusion, a novel series of 1,2,4-triazole-thiol derivatives has been developed as potent inhibitor of PI3K/mTOR against lung cancer with favorable drug likeness profile.
Clinical trial identification:
Legal entity responsible for the study:
SHUATS
Funding:
SHUATS
Disclosure:
All authors have declared no conflicts of interest.
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42P - Dual inhibitory effects of novel naringenin analogue in tobacco-carcinogen induced lung cancer via inhibition of PI3K/Akt/mTOR pathway (ID 337)
12:30 - 13:00 | Author(s): A. Verma
- Abstract
Background:
Phosphoinositide 3- kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathways is considered as the signalling pathway which activates the diverse cellular function viz., survival, cell expansion, vesicular transport and proliferation and found frequently dysregulated pathway in lung cancer. Consequently, flavonoids based inhibitors play a key kinase role in the pathway including mTOR, PI3K and AKT, have been extensively scrutinized in targeting the oncology in recent years. The common pathway to PI3K-Akt-mTOR used to target during the lung cancer therapy. Therefore, the current study was aimed to peruse the naringenin as dual PI3K/mTOR for lung cancer.
Methods:
In the current experimental study mice were randomly divided into 7 groups with 12 mice in each groups The oxidative stress was evaluated in term of antioxidant parameters such as myeloperoxidase (MPO) and superoxide dismutase (SOD), respectively. The proinflammatory cytokines viz., interleukin (IL)-1β, tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 were measured via using the standard enzyme-linked immunosorbent assay kits. The concentration of PI3K, P-PI3K, mTOR, P-mTOR Akt and P-Akt were determined via using the Western blot techniques. We also performed the histopathological study to identify the changes during the disease.
Results:
Naringenin significantly suppressed the oxidative stress via improving the status of endogenous antioxidant parameters such as SOD and MPO in a dose dependent manner. disease control group mice confirmed the change in protein levels of PI3K/Akt/mTOR pathway in lung as compared to normal control, which were significantly down-regulated by the naringenin in a dose dependent manner. In the histological study, we observed that the naringenin substantially reduced the benzopyrene induced neutrophils in lung tissue.
Conclusions:
It can be concluded that naringenin has shown promising anticancer effect via attenuation of PI3K/Akt/mTOR against lung cancer and signifies the potential therapeutic relevance for further development.
Clinical trial identification:
Legal entity responsible for the study:
SHUATS
Funding:
SHUATS
Disclosure:
All authors have declared no conflicts of interest.
