PQR530 is an Orally Active and Brain-Penetrant Dual PI3K, mTORC1/2 Inhibitor

Several brain disorders, such as epilepsy, found dysregulation of the PI3K/Akt/mTOR pathway. The PI3K-AKT/mTOR pathway is a central player of intracellular signaling, regulating neuronal survival, growth, and plasticity. Aberrant activation of this signaling pathway drives the progression of malignant tumors. The mutation of growth factor receptors, PI3K, loss of PTEN, and effector proteins such as Ras can trigger the signaling pathway. Drugs, targeting the pathway at multiple nodes, such as the PI3K/mTOR inhibitor BEZ235, show promising preclinical results attenuating tumor growth specifically due to PI3K overexpression. They also block the growth of cancer cells with multiple activated pathways, such as in melanoma. In this study, PQR530 is a potent, ATP-competitive, orally bioavailable, and brain-penetrant dual pan-PI3K/mTORC1/2 inhibitor. It displays a subnanomolar K_d toward PI3Kα and mTOR (0.84 and 0.33 nM, respectively). It also has antitumor activity.

PQR-530 is a potent, oral and brain-penetrant dual pan-PI3K/mTORC1/2 inhibitor, exhibiting antitumor activity. PQR-530 inhibits all PI3K isoforms and mTOR complexes C1/2 potently and selectively. It also inhibits protein kinase B (PKB, pSer473) and ribosomal protein S6 (pS6, pSer235/236) phosphorylation, with IC₅₀ values of 0.07 µM in A2058 melanoma cells. PQR-530 shows inhibitory activity against the growth of 44 cancer cell lines with mean GI₅₀ of 426 nM. In addition, it shows excellent selectivity over a wide panel of kinases, and also shows an excellent selectivity against other receptor enzymes and ion channels. Moreover, it prevents cell growth in a cancer cell line panel. Furthermore, PQR-530 demonstrates good oral bioavailability, excellent brain penetration, and efficacy in an OVCAR-3 xenograft model.

In summary, QR530 is a potent, ATP-competitive, orally bioavailable, and brain-penetrant dual pan-PI3K/mTORC1/2 inhibitor. It is a therapeutic agent in oncology.

Reference:

Rageot D, et al.  J Med Chem. 2019;62(13):6241-6261.;Denise Rageot, et al. Cancer Res 2017;77(13 Suppl).