Biological target:
Omipalisib (GSK2126458) is an orally active and highly selective inhibitor of PI3K and has anti-cancer activity. Omipalisib has Kis of 0.019 nM/0.13 nM/0.024 nM/0.06 nM and 0.18 nM/0.3 nM for p110α/β/δ/γ, mTORC1/2, respectively.
In vitro activity:
Many dual catalytic mTOR inhibitors do not have tolerable clinical profiles, [14] so this study investigated a clinically acceptable dual PI3K/mTOR inhibitor omipalisib (GSK2126458) [15] that has completed a Phase 1 clinical trial in patients with advanced solid tumors [16] and another Phase 1 trial in patients with idiopathic pulmonary fibrosis [17]. Cell lines were grown in DMEM media (Corning, Manassas, VA, USA) supplemented with 100 U/mL penicillin, 100 μg/mL streptomycin (Gibco, Gaithersburg, MA, NY, USA), 10 mM glutamine, and 10% fetal bovine serum (FBS) (Atlanta Biologicals, Atlanta, GA, USA) and were maintained at 37 °C in a humidified atmosphere with 5% CO2. Omipalisib (GSK2126458) was obtained from MedKoo Sciences (Morrisville, NC, USA). Stocks were made in DMSO (Sigma-Aldrich, St. Louis, MO, USA) 1–100 mM and stored in aliquots at −20 °C, prior to appropriate dilution for inhibition studies.The PI3K/mTOR inhibitor effectively reduced phosphorylation of S6, 4E-BP1, Akt and, in an additive manner with rapamycin, inhibited cell growth. Our study demonstrated that omipalisib dose-dependently inhibits pAkt and both mTORC1 protein synthetic pathways and, in an additive manner with rapamycin, inhibited the growth of TSC2-null cells. Omipalisib, or another inhibitor of both major mTORC1 growth pathways and pAkt, might provide therapeutic options for TSC2-deficient cancers including, but not limited to, LAM.We suggest that a clinically tolerable PI3K/mTOR inhibitor might be beneficial in LAM, as monotherapy or in combination with rapamycin, and in other mTORC1-driven neoplastic diseases.
Biomolecules. 2020 Jan; 10(1): 28.Published online 2019 Dec 24. doi: 10.3390/biom10010028
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022412/
In vivo activity:
This study aimed to investigate the antineoplastic effects of omipalisib and its underlying molecular mechanisms in ESCC using a high throughput screen. MTT assay and clone formation were used to determine cell viability and proliferation. Flow cytometry was conducted to detect cell cycle distribution and apoptosis. Global gene expression and mRNA expression levels were determined by RNA sequencing and real-time PCR, respectively. Protein expression was evaluated in the 4 ESCC cell lines by Western blot analysis. Finally, a xenograft nude mouse model was used to evaluate the effect of omipalisib on tumor growth in vivo. In the pilot screening of a 1404-compound library, we demonstrated that omipalisib markedly inhibited cell proliferation in a panel of ESCC cell lines. Mechanistically, omipalisib induced G0/G1 cell cycle arrest and apoptosis. RNA-seq, KEGG, and GSEA analyses revealed that the PI3K/AKT/mTOR pathway is the prominent target of omipalisib in ESCC cells. Treatment with omipalisib decreased expression of p-AKT, p-4EBP1, p-p70S6K, p-S6, and p-ERK, therefore disrupting the activation of PI3K/AKT/mTOR and ERK signaling. In the nude mouse xenograft model, omipalisib significantly suppressed the tumor growth in ESCC tumor-bearing mice without obvious adverse effects.
Med Sci Monit. 2020; 26: e927106-1–e927106-13.Published online 2020 Aug 17. Prepublished online 2020 Aug 11. doi: 10.12659/MSM.927106
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450785/
