mTOR-IN-1

mTOR-IN-1 is a remarkably selective mTOR inhibitor with a Ki of 1.5 nM. mTOR-IN-1 suppresses mTORC1 and mTORC2 in cellular and in vivo pharmacokinetic (PK)/pharmacodynamic (PD) experiments.

Research Areas >> Cancer

mTOR:1.5 nM (Ki)

mTORC1

mTORC2

mTOR-IN-1 (Compound 12i) inhibits mTOR with a Ki of 1.5 nM, 500-fold selectivity over closely related PI3 kinases. mTOR-IN-1 inhibits NCI-PC3 and MCF7neo/Her2 cells proliferation with IC50s of 150 nM and 57 nM, respectively[2].

mTOR-IN-1 (Compound 8h) has high free plasma clearance in both mice (1818 mL/min/kg) and rats (1538 mL/min/kg in rat) [1]. mTOR-IN-1 (Compounds 12i) is selected for this study due to its potency, selectivity, and favorable mouse PK profile. Plasma levels of mTOR-IN-1 6 h following oral administration in PC3 tumor-bearing mice along with the fold decreases of phosphorylated mTORC1 and -2 substrates relative to time-matched vehicle controls. mTOR-IN-1 has moderate terminal elimination half-life (t1/2=1.7 h for mouse(1 mg/kg, iv)). mTOR-IN-1 achieves tumor stasis at the highest 200 mg/kg/day dose examined, which appears to also be approaching the limit of tolerability for this molecule[2].

Mice[2] Human prostate cancer NCI-PC3 cells are implanted subcutaneously into the right hind flanks of female NCR nude mice (5×106 cells in 100 μL of Hank’s balanced salt solution). Tumors are monitored until they reach a mean tumor volume of approximately 500 mm3. Then similarly sized tumors are randomly assigned to groups (n=4). Compounds are formulated as suspensions in 0.5% methylcellulose/0.2% Tween 80 (MCT) and dosed orally at 25, 50, and 100 mg/kg (100 μL dose/25 g animal). Tumor and plasma samples are harvested at 1, 6, and 10 h postdose.

[1]. Pei Z, et al. Discovery and Biological Profiling of Potent and Selective mTOR Inhibitor GDC-0349. ACS Med Chem Lett. 2012 Nov 29;4(1):103-7.

[2]. Koehler MF, et al. Potent, selective, and orally bioavailable inhibitors of the mammalian target of rapamycin kinase domain exhibiting single agent antiproliferative activity. J Med Chem. 2012 Dec 27;55(24):10958-71.

Rapamycin (Sirolimus) | Torin 1 | MHY1485 | Sapanisertib (MLN0128) | AZD8055 | Dactolisib (BEZ235) | Vistusertib (AZD2014) | Torkinib (PP242) | LY3023414 | Torin 2 | GSK2126458(GSK458) | PF-04691502 | Salidroside | PQR-309 | OSI-027