PQR309

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.

PQR309 是一种有效的脑渗透性口服生物利用度泛 I 类 PI3K/mTOR 抑制剂，对 PI3Kα、PI3Kδ、PI3Kβ、PI3Kγ 和 mTOR 的 IC50 分别为 33nM、451nM、661nM、708nM 和 89nM ^[1][2].

PQR309 在人脑胶质瘤细胞中通过抑制增殖、诱导细胞凋亡、诱导 G1 细胞周期停滞、抑制侵袭和迁移等方式发挥抗肿瘤作用^[3]。 PQR309 通过减少 CDK6 和增加 p27 并随后诱导 G1 期停滞来减少子宫内膜癌细胞和子宫内膜癌干细胞的增殖。 PQR309 对 c-Myc/mtp53 级联的抑制在抗子宫内膜癌中起着关键作用。 PQR309可能是一种潜在的抗子宫内膜癌药物^[4]

PQR309 在体外和体内作为单一药物和联合药物均具有抗淋巴瘤活性^[5]。 PQR309 在 50 例经过大量预处理的各种组织学亚型的复发性或难治性淋巴瘤患者中以 80 毫克和 60 毫克的连续剂量^[6]显示出仅适度的反应，但显示出显着的毒性。 PQR309 的 MTD 和 RP2D 为 80 mg 口服 OD^[2]