P7170, a novel inhibitor of mTORC1/mTORC2 and Activin receptor-like Kinase 1 (ALK1) inhibits the growth of non small cell lung cancer

Venkatesha, Venkatasubbaiah A.; Joshi, Asavari; Magesh, V.; Sonawane, Vinay R.; Bhatia, Dimple; Tannu, Prashant; Bose, Julie; Choudhari, Sarika; Srivastava, Ankita; Pandey, Prashant; Lad, V J; Sangana, Ramachandra; Ahmed, Tausif; Damre, Anagha; Deore, Vijaykumar; Sahu, Bichismita; Kumar, Sanjay; Sharma, Somesh; Agarwal, Veena R.

doi:10.1186/1476-4598-13-259

Cited by 10 publications

(9 citation statements)

References 28 publications

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“…In our study, we found similar anti-proliferative effects of VJ by combined inhibition on EGFR/AKT/mTOR axis by VJ treatment in both A549 and H460 cell lines. Similar results were reported of how simultaneous inhibition of pAKT expression and mTOR phosphorylation resulted in decreased survival of NSCLC cells and inhibition of tumor growth in vivo [ 44 ]. AKT has been shown to activate a major subunit of NF-κB, RelA [ 45 ], thus we examined whether inhibition of AKT activation affects NF-κB expression in lung cancer cells.…”

Section: Discussionsupporting

confidence: 87%

Molecular insights: Suppression of EGFR and AKT activation by a small molecule in non-small cell lung cancer

et al. 2017

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Epidermal growth factor receptor (EGFR) activation events and the mammalian target of rampamycin (mTOR) are considered important therapeutic targets in alleviating cancer conditions. The current treatment paradigm has shifted to personalized treatment strategies with tyrosine kinase inhibitors (TKIs) or anaplastic lymphoma kinase (ALK) inhibitors, due to low survival rates in non-small cell lung cancer (NSCLC) in terms of the prevailing platinum-based therapy. In the present study, we examined the anticancer potential of Verrucarin J (VJ), a small molecule, in NSCLC cell lines (H460 and A549). The small molecule significantly inhibited cell growth, proliferation, colony forming ability, and induced apoptosis in both lung cancer cell lines. The inhibitory effects on EGFR (pEGFR –tyr1173) and AKT (pAKT Serine473) signaling, downregulates downstream pro-survival signaling (mTOR and NF-κB) in cancer cell lines. In addition, VJ abrogated invasive and migratory potential of A549 and H460 cells. We also observed a downregulation of mesenchymal markers such as N-cadherin, Slug, β-catenin, and vimentin expression in both cell lines. Our results suggest that VJ inhibited cancer cell growth and could be a potent molecule to inhibit EGFR and AKT signaling in NSCLC.

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Section: Discussionsupporting

confidence: 87%

Molecular insights: Suppression of EGFR and AKT activation by a small molecule in non-small cell lung cancer

et al. 2017

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“…Moreover, we did not evaluated sufficient doses of INK128 to determine the therapeutic window, a critical parameter to determine its potential clinical utility of TOR-KIs against HIV. Future studies should determine the therapeutic window and dosing schedules for INK128 and additional TOR-KIs (18,(49)(50)(51)(52)(53)(54) so as to identify the most effective and safest approach to inhibit HIV.…”

Section: Discussionmentioning

confidence: 99%

Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice

Heredia

Gartenhaus

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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HIV necessitates host factors for successful completion of its life cycle. Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that forms two complexes, mTORC1 and mTORC2. Rapamycin is an allosteric inhibitor of mTOR that selectively inhibits mTORC1. Rapamycin interferes with viral entry of CCR5 (R5)-tropic HIV and with basal transcription of the HIV LTR, potently inhibiting replication of R5 HIV but not CXCR4 (X4)-tropic HIV in primary cells. The recently developed ATP-competitive mTOR kinase inhibitors (TOR-KIs) inhibit both mTORC1 and mTORC2. Using INK128 as a prototype TOR-KI, we demonstrate potent inhibition of both R5 and X4 HIV in primary lymphocytes (EC50 < 50 nM), in the absence of toxicity. INK128 inhibited R5 HIV entry by reducing CCR5 levels. INK128 also inhibited both basal and induced transcription of HIV genes, consistent with inhibition of mTORC2, whose activity is critical for phosphorylation of PKC isoforms and, in turn, induction of NF-κB. INK128 enhanced the antiviral potency of the CCR5 antagonist maraviroc, and had favorable antiviral interactions with HIV inhibitors of reverse transcriptase, integrase and protease. In humanized mice, INK128 decreased plasma HIV RNA by >2 log10 units and partially restored CD4/CD8 cell ratios. Targeting of cellular mTOR with INK128 (and perhaps others TOR-KIs) provides a potential strategy to inhibit HIV, especially in patients with drug resistant HIV strains.

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“…This quinoline compounds demonstrated potent inhibition activity on mTORC1/mTORC2/ALK1, cell cycle arrest, induction of apoptosis, antiangiogenic activity. Moreover, it showed antitumor efficacy on both in vitro and in vivo studies against the erlotinib–sensitive and –insensitive models NSCLC and anti-estrogen models of ER+ breast cancer [ 86 , 87 , 88 ], reaching the clinical trials evaluation for patients with advanced refractory solid tumours ( number NCT01762410) [ 89 ].…”

Section: Quinolines As Inhibitors Of Carcinogenic Pathwaysmentioning

confidence: 99%

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

2020

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The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, antipsychotic, and anticancer drugs. In drug discovery, indeed, over the last few years, an increase in the publication of papers and patents about quinoline derivatives possessing antiproliferative properties has been observed. This trend can be justified by the versatility and accessibility of the quinoline scaffold, from which new derivatives can be easily designed and synthesized. Within the numerous quinoline small molecules developed as antiproliferative drugs, this review is focused on compounds effective on c-Met, VEGF (vascular endothelial growth factor), and EGF (epidermal growth factor) receptors, pivotal targets for the activation of important carcinogenic pathways (Ras/Raf/MEK and PI3K/AkT/mTOR). These signalling cascades are closely connected and regulate the survival processes in the cell, such as proliferation, apoptosis, differentiation, and angiogenesis. The antiproliferative biological data of remarkable quinoline compounds have been analysed, confirming the pivotal importance of this ring system in the efficacy of several approved drugs. Furthermore, in view of an SAR (structure-activity relationship) study, the most recurrent ligand–protein interactions of the reviewed molecules are summarized.

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P7170, a novel inhibitor of mTORC1/mTORC2 and Activin receptor-like Kinase 1 (ALK1) inhibits the growth of non small cell lung cancer

Cited by 10 publications

References 28 publications

Molecular insights: Suppression of EGFR and AKT activation by a small molecule in non-small cell lung cancer

Molecular insights: Suppression of EGFR and AKT activation by a small molecule in non-small cell lung cancer

Targeting of mTOR catalytic site inhibits multiple steps of the HIV-1 lifecycle and suppresses HIV-1 viremia in humanized mice

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

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