Cell lines

Human GBM cell lines (U87 and U251)

Preparation Method

5x10³cells were seeded in 96-well plate, and PQR309 was added into each well. Various concentrations of PQR309 (0, 1, 5, 10, 20, 50 and 100μM), as well as a certain concentration applied for different time-points (24, 48, 72 and 96h) were evaluated. Next, 10μL CCK-8 was added, and the cells were incubated for 1 h at 37℃.

Reaction Conditions

0, 1, 5, 10, 20, 50 and 100μM

Applications

PQR309 had a significant suppressive effect on U87 and U251 cells. The viability of the cells was significantly (P50values of PQR309 were 7.104 (95% CI, 5.6-8.5) and 11.986 (95% CI, 10.6-13.4) in U87 and U251 cells, respectively.

Animal models

Healthy male nude NIH rats

Preparation Method

Rats were injected with 2×10⁷human PC3 prostate cancer cells into one flank and randomized after 16 days. From day 17, PQR309 was orally administered at 5mg/kg, 10mg/kg (both daily, QD), or 15mg/kg [5 consecutive days, 2 days off drug (QD×5, 2 days off)] for 28 days to match the timelines of regulatory toxicology studies.

Dosage form

5, 10, 15mg/kg, oral administration

Applications

Treatment with PQR309 led to significant tumor size reductions: tumor growth was inhibited dose-dependently (best T/C of 31-12%). PQR309 was best tolerated at 5mg/kg without significant body weight changes. At 10mg/kg, PQR309 caused a reduction of body weight, which accumulated to a reduction of 15% after 28 days of treatment. Similarly,15 mg/kg of PQR309 led to body weight loss after 5 days of treatment, which was reversible during the recovery period. After 28 days of drug exposure, animals with body weight loss fully recovered within a treatment-free period (days 45-50) without overt signs of tumor cell proliferation.

PQR309 is a potent, brain-penetrant, orally bioavailable, pan-class I PI3K/mTOR inhibitor with IC50s of 33nM, 451nM, 661nM, 708nM and 89nM for PI3Kα, PI3Kδ, PI3Kβ, PI3Kγ and mTOR, respectively^[1][2].

PQR309 exerts an antitumor effect by inhibiting proliferation, inducing apoptosis, inducing G1 cell cycle arrest, and inhibiting invasion and migration in human glioma cells^[3]. PQR309 reduces proliferation in endometrial cancer cells and endometrial cancer stem cells by decreasing CDK6 and increasing p27 and subsequently inducing G1-phase arrest. Inhibition of c-Myc/mtp53 cascade played a critical role in anti-endometrial cancer by PQR309. PQR309 may be a potential drug in anti-endometrial cancer^[4]

PQR309 has anti-lymphoma activity as single agent and in combination in vitro and in vivo^[5]. PQR309 shows only modest response but significant toxicity in 50 patients with heavily pretreated relapsed or refractory lymphoma of various histological subtype at continuous doses of 80mg and 60mg^[6]. The MTD and RP2D of PQR309 is 80 mg of orally OD^[2]

References:
[1]. Beaufils F, Cmiljanovic N, 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 Med Chem. 2017;60(17):7524-7538.
[2]. Wicki A, Brown N, et al. First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with advanced solid tumors (SAKK 67/13). Eur J Cancer. 2018;96:6-16.
[3]. Yang K, Tang XJ, et al. PI3K/mTORC1/2 inhibitor PQR309 inhibits proliferation and induces apoptosis in human glioblastoma cells. Oncol Rep. 2020;43(3):773-782.
[4]. Hsin IL, Shen HP, 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. Cells. 2021;10(11):2916. Published 2021 Oct 27.
[5]. Tarantelli C, Gaudio E, et al. PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy. Clin Cancer Res. 2018;24(1):120-129.
[6]. Collins GP, Eyre TA, 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. Hemasphere. 2021;5(11):e656. Published 2021 Oct 27.