GSK2126458 (Omipalisib) is an orally active and highly selective inhibitor of PI3K with Ki values of 0.019nM/0.13nM/0.024nM/0.06nM and 0.18nM/0.3nM for p110α/β/δ/γ, mTORC1/2, respectively[1]. GSK2126458 targets the PI3K/Akt/mTOR pathway, reducing the glycolytic activity of cancer cells and causing metabolic disorders in the cells, thereby inhibiting the growth of cancer cells[2]. GSK2126458 has been widely used in cancer research as a radiosensitizer or chemosensitizer to efficiently kill cancer cells[3].
In vitro, GSK2126458 treatment for 72 hours significantly inhibited the viability of A549, HCT116 and MDA-MB-231 cells, with IC50 values of 0.6µM, 0.01µM, and 0.13µM, respectively[4]. Treatment with 160nM GSK2126458 for 24 hours induced cell cycle arrest in esophageal squamous cell carcinoma (ESCC) cells, accompanied by a decrease in CCND1 expression and an increase in the number of apoptotic cells[5]. Treatment with 10µM GSK2126458 for 48 hours led to cell death and autophagy in C76N cells and increased the expression of Atg12, LC3A and LC3B[6]. Incubation with 50nM GSK2126458 for 24 hours downregulated the genes related to amino acid metabolism and mitochondrial biosynthesis in OCI-AML3 cells, and inhibited mitochondrial respiration[7].
In vivo, GSK2126458 treatment via oral administration at a dose of 1mg/kg twice daily for 7 days prolonged the cardiac repolarization in the canine model of atrioventricular block, accompanied by a mild proarrhythmic outcome[8]. Daily intraperitoneal injection of GSK2126458 (1mg/kg) for 2 months reduced the overphosphorylated tau protein expression and mitigated spatial memory deficits in tau P301S (1N4R) mutant (PS19) male mice[9].
References:[1] Knight S D, Adams N D, Burgess J L, et al. Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin[J]. ACS medicinal chemistry letters, 2010, 1(1): 39.
[2] Bye B A, Jack J L, Pierce A, et al. Combined omipalisib and MAPK Inhibition suppress PDAC growth[J]. Cancers, 2025, 17(7): 1152.
[3] Du J, Chen F, Yu J, et al. The PI3K/mTOR inhibitor ompalisib suppresses nonhomologous end joining and sensitizes cancer cells to radio-and chemotherapy[J]. Molecular Cancer Research, 2021, 19(11): 1889-1899.
[4] Chen Y, Zhang L, Yang C, et al. Discovery of benzenesulfonamide derivatives as potent PI3K/mTOR dual inhibitors with in vivo efficacies against hepatocellular carcinoma[J]. Bioorganic & medicinal chemistry, 2016, 24(5): 957-966.
[5] Zhu D, Dong J, Xu Y, et al. Omipalisib inhibits esophageal squamous cell carcinoma growth through inactivation of phosphoinositide 3-Kinase (PI3K)/AKT/Mammalian target of rapamycin (mTOR) and ERK signaling[J]. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research, 2020, 26: e927106-1.
[6] Basu D, Salgado C M, Bauer B, et al. The dual PI3K/mToR inhibitor omipalisib/GSK2126458 inhibits clonogenic growth in oncogenically-transformed cells from neurocutaneous melanocytosis[J]. Cancer Genomics-Proteomics, 2018, 15(4): 239-248.
[7] Tseng C Y, Fu Y H, Ou D L, et al. Anti-leukemia effects of omipalisib in acute myeloid leukemia: inhibition of PI3K/AKT/mTOR signaling and suppression of mitochondrial biogenesis[J]. Cancer Gene Therapy, 2023, 30(12): 1691-1701.
[8] van Bavel J J A, Pham C, Beekman H D M, et al. PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model[J]. Frontiers in cardiovascular medicine, 2022, 9: 956538.
[9] Hwang H, Kim N, Jeon S, et al. Omipalisib reduces hyperphosphorylated tau protein by modulating mTOR-autophagy pathway[J]. Plos one, 2026, 21(6): e0352120.