PQR309 is a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor with IC50 values of 33nM, 451nM, 661nM, 708nM and 89nM for PI3Kα, PI3Kδ, PI3Kβ, PI3Kγ and mTOR, respectively[1]. PQR309 induces cell cycle arrest by inhibiting the positive feedback loop of PI3K/Akt/mTOR/c-Myc/mtp53 and reducing the expression of CDK6 while increasing the expression of p27[2]. PQR309 has been widely used in tumor research to restrain lymphoma development in different cell lines and animal models[3].
In vitro, PQR309 treatment for 72 hours significantly suppressed the proliferation of U87 and U251 cells, with IC50 values of 7.104μM and 11.986μM, respectively[4]. 500nM of PQR309 treatment for 72 hours induced apoptosis in diffuse large B-cell lymphoma (DLBCL) cells and decreased the level of p-AKT[5]. Treatment with 2μM PQR309 for 72 hours induced senescence in LN-229 cells, accompanied by an increase in β-galactosidase activity[6].
In vivo, PQR309 treatment via oral administration at a dose of 50mg/kg/day for 15 days inhibited tumor growth in the CNE1 xenograft mouse model and reduced the protein levels of p-STAT3, HSP60, and p-GSK-3β in tumor tissues[7].
References:
[1] Beaufils F, Cmiljanovic N, Cmiljanovic V, et al. 5‑(4, 6-Dimorpholino-1, 3, 5-triazin-2-yl)-4-(trifluoromethyl) pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology[J]. Journal of medicinal chemistry, 2017, 60(17): 7524-7538.
[2] Hsin I L, Shen H P, Chang H Y, et al. Suppression of PI3K/Akt/mTOR/c-Myc/mtp53 positive feedback loop induces cell cycle arrest by dual PI3K/mTOR inhibitor PQR309 in endometrial cancer cell lines[J]. Cells, 2021, 10(11): 2916.
[3] Collins G P, Eyre T A, Schmitz‐Rohmer D, et al. A phase II study to assess the safety and efficacy of the dual mTORC1/2 and PI3K inhibitor bimiralisib (PQR309) in relapsed, refractory lymphoma[J]. Hemasphere, 2021, 5(11): e656.
[4] Yang K, Tang X J, Xu F F, et al. PI3K/mTORC1/2 inhibitor PQR309 inhibits proliferation and induces apoptosis in human glioblastoma cells[J]. Oncology Reports, 2020, 43(3): 773-782.
[5] Tarantelli C, Gaudio E, Kwee I, et al. The novel PI3K/mTOR dual inhibitor PQR309 in pre-clinical lymphoma models: Demonstration of anti-tumor activity as single agent and in combination and identification of gene expression signatures associated with response[J]. Blood, 2014, 124(21): 1782.
[6] von Achenbach C, Weller M, Kaulich K, et al. Synergistic growth inhibition mediated by dual PI3K/mTOR pathway targeting and genetic or direct pharmacological AKT inhibition in human glioblastoma models[J]. Journal of neurochemistry, 2020, 153(4): 510-524.
[7] Cao J, Zeng K, Chen Q, et al. PQR309, a dual PI3K/mTOR inhibitor, synergizes with gemcitabine by impairing the GSK-3β and STAT3/HSP60 signaling pathways to treat nasopharyngeal carcinoma[J]. Cell death & disease, 2024, 15(3): 237.