XL388 / Exelixis - LARVOL DELTA

Virtual docking screening and quantitative structure-activity relationship studies to explore AKT and PI3K inhibitors acting on mTOR in cancers by theoretical biology and medical modeling. (PubMed, Contemp Oncol (Pozn)) - "The mechanistic target of rapamycin (mTOR) coordinates the growth and metabolism of eukaryotic cells with a central role in the regulation of many fundamental cellular processes. The best predicted AKT and PI3K inhibitor pIC50 activities were 9.36-9.95 and 9.23-9.87 respectively. After docking and several comparisons, the inhibitors with better predictions showed better affinity and interaction with mTOR compared to AZ8055 and XL388, so we have found that 2 AKT inhibitors and 9 mTOR inhibitors met the Lipinski and Veber criteria and could be future drugs."

Journal • Oncology

mTOR regulates stem cells of glioblastoma by altering the self-renewal and proliferation (AACR 2023) - "GBM stem cells were treated with various inhibitors of canonical PI3K/AKT/mTOR pathways such as rapamycin (mTORC1 inhibitor), PP242 (ATP binding mTORC1/2 inhibitor), LY294002 (PI3K inhibitor), and MAPK inhibitor, U0126...Treatment with novel small molecule dual inhibitors of mTORC1/2 demonstrated that Torin1 and Torin2 suppressed the proliferation of GBM CSC, while XL388 was less effective...Additionally, Torin2 was able to eradicate tumor cells. Torin2 effectively targeted CSCs of GBM by halting self-renewal and inhibiting cell proliferation, underscoring the use of Torin2 in the treatment of GBM."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • NANOG • NES • PTEN

Defining the role of mTOR pathway in the regulation of stem cells of glioblastoma. (PubMed, Adv Biol Regul) - "Here we explored the role of the mTOR pathway in the regulation of stem cells of GBM by treating them with inhibitors of canonical PI3K/AKT/mTOR pathways such as rapamycin (mTORC1 inhibitor), PP242 (ATP binding mTORC1/2 inhibitor), LY294002 (PI3K inhibitor), and MAPK inhibitor, U0126...Treatment with novel small molecule inhibitors of mTORC1/2 demonstrated that Torin1 and Torin2 suppressed the proliferation of GBM CSC, while XL388 was less effective...Torin2 was able to eradicate tumor cells. In conclusion, Torin2 effectively targeted CSCs of GBM by halting self-renewal and inhibiting cell proliferation, underscoring the use of Torin2 in the treatment of GBM."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • NANOG • NES • PTEN

First, second, and third generation mTOR pathways inhibitors for treatment of glioblastoma (AACR 2022) - "These results suggested that RAPA, Torin1, Torin2, and Rapalink-1, but not XL388, are useful in suppressing the mTORC1 and mTORC2 activities, thereby inhibiting GB cell proliferation, dissemination, and inhibiting stem cell self-renewal. Therefore, the use of these mTOR inhibitors presents a promising treatment strategy for Glioblastoma."

Brain Cancer • Glioblastoma • Oncology • Solid Tumor • AKT1S1 • EIF4EBP1 • NES • PTEN

Disentangling the signaling pathways of mTOR complexes, mTORC1 and mTORC2, as a therapeutic target in glioblastoma. (PubMed, Adv Biol Regul) - "Since rapamycin and it's analogue are less effective in treatment of GB, we used novel ATP-competitive dual inhibitors of mTORC1 and mTORC2, namely, Torin1, Torin2, and XL388. In addition, formulation of third generation mTOR inhibitor "Rapalink-1" may provide new aspects to target mTOR pathways. Numerous inhibitors are currently being used in clinical trials that are aimed to target activated mTOR pathways."

Journal • Review • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • AKT1S1 • EIF4EBP1 • PTEN

Targeting the mTOR pathway using novel ATP‑competitive inhibitors, Torin1, Torin2 and XL388, in the treatment of glioblastoma. (PubMed, Int J Oncol) - "These results strongly suggest that Torin2, compared to Torin1 or XL388, is more effective in suppressing mTORC1 and mTORC2, and therefore in the inhibition of the GB cell proliferation, dissemination and in overcoming resistance to therapy. These findings underscore the significance of Torin2 in the treatment of GB."

Journal • Brain Cancer • Glioblastoma • Oncology • Solid Tumor • AKT1S1 • EIF4E • EIF4EBP1 • PTEN

Manganese-enhanced MRI depicts a reduction in brain responses to nociception upon mTOR inhibition in chronic pain rats. (PubMed, Mol Brain) - "At day 7 after nerve injury, drugs were applied into the intracortical area, and drug (Vehicle, Torin1, and XL388) effects were compared within groups using MEMRI. Furthermore, rostral-caudal analysis of the IC indicated that the rostral region of the IC was more strongly associated with pain perception than the caudal region. Our data suggest that MEMRI can depict pain-related signal changes in the brain and that mTOR inhibition is closely correlated with pain modulation in chronic pain rats."

Journal • Neuralgia • Pain • Peripheral Neuropathic Pain • MRI

The therapeutic value of XL388 in human glioma cells. (PubMed, Aging (Albany NY)) - "Akt-S6K1 inhibition and MAFG downregulation were detected in XL388-treated A172 xenograft tissues. Collectively, XL388 efficiently inhibits human glioma cell growth, through Akt-mTOR-dependent and -independent mechanisms."

Journal • Glioma • Oncology • Solid Tumor • AKT1

Effects of mTOR inhibitors on neuropathic pain revealed by optical imaging of the insular cortex in rats. (PubMed, Brain Res) - "However, there were no significant optical signal changes in the IC before and after vehicle application. These findings suggested that Torin1 and XL388 are associated with the alleviation of neuronal activity that is excessively manifested in the IC, and is assumed to diminish synaptic plasticity."

Journal • Preclinical

mTOR signaling intervention by Torin1 and XL388 in the insular cortex alleviates neuropathic pain. (PubMed, Neurosci Lett) - "At the immunoblotting results, Torin1 and XL388 significantly reduced phosphorylation of mTOR, 4E-BP1, p70S6K, and PKCα, without affecting Akt. These results strongly suggest that Torin1 and XL388 may attenuate neuropathic pain via inhibition of mTORC1 and mTORC2 in the IC."

Journal • EIF4EBP1