9-(6-Amino-3-pyridinyl)-1-[3-(trifluoromethyl)phenyl]benzo[h]-1,6-naphthyridin-2(1H)-one

Description

Torin 2 is a potent and selective mTOR inhibitor with IC50 of 0.25 nM in p53?/? MEFs cell line; 800-fold greater selectivity for mTOR than PI3K and improved pharmacokinetic properties. Inhibition of ATM/ATR/DNA-PK with EC50 of 28 nM/35 nM/118 nM,in PC3 cell lines respectively.

In vitro

Torin 2 has the same binding mode as PI3Kγ, V882 serves as a hinge binding point and in the inner hydrophobic pocket Y867, D841 and D964 provide three more hydrogen bonds with aminopyridine side chain analogous to Y2225, D2195 and D2357 of mTOR. Torin 2 inhibits mTORC1, thus activates TFEB by promoting its nuclear translocation with EC50 of 1.666 mM. Torin 2(< 50 nM) causes a significant reduction in viability of both MZ-CRC-1 and TT cells. Torin 2 (100 nM) exerts a significant reduction of migration of both MZ-CRC-1 and TT cells.

In vivo

Torin 2 exhibits >95% pharmacodynamic response and half-time of 11.7 min in the mouse liver microsome stability study. Torin 2 exhibits the best bioavailability (51%), short half-life (0.72 hours) and low clearance(19.6 mL/min/kg) in male Swiss albino mice following intravenous and oral administration. Torin 2(20mg/kg) ablates MYCN tumors with reduction in MYCN protein levels and induction of apoptosis in Th-MYCN mice.

Description

Torin 2 is a potent and selective inhibitor of cellular mTOR activity (EC₅₀ = 0.3 nM). It shows more than 800-fold selectivity for mTOR over PI3K (EC₅₀ = 200 nM) and greater than 100-fold binding selectivity relative to 440 other protein kinases. Torin 2 has significantly improved bioavailability (54%), metabolic stability, and plasma exposure compared to torin 1 .

Uses

Torin 2 is a potent, selective, and orally available mammalian target of rapamycin (mTOR) inhibitor for treatment of cancer.

Uses

Torin2 has been used:

• to examine its effect on LC3B-II levels in BORCS5- KO cells
• to determine its potent activity (IC₅₀less than 1 μM) against A2780-cis ovarian cancer cells
• in western blot analysis

Definition

ChEBI: Torin 2 is a member of the class of pyridoquinolines that is benzo[h][1,6]naphthyridin-2-one carrying additional 3-(trifluoromethyl)phenyl and 6-aminopyridin-3-yl substituents at positions 1 and 9 respectively. It is a potent inhibitor of mTOR and exhibits anti-cancer properties. It has a role as a mTOR inhibitor and an antineoplastic agent. It is an organofluorine compound, a pyridoquinoline, an aminopyridine and a primary amino compound.

Biochem/physiol Actions

Torin2 is a highly potent and selective ATP-competitive mTOR inhibitor. Torin2 has an IC50 of 0.25 nM and 800-fold greater selectivity for mTOR than PI3K.

storage

Store at +4°C

Background

Torin 2 is a potent and selective ATP-competitive mTOR inhibitor with superior pharmacokinetics over the Torin 1 predecessor. A series of in vitro kinase activity assays indicate that Torin 2 inhibits mTORC1 with an IC50 of 2.1 nM. Cellular activity assays demonstrate that Torin 2 inhibits cellular mTOR activity with an EC50 of 0.25 nM. These assays also indicate that Torin 2 has an 800-fold selectivity over P13K and a over 800-fold selectivity over 400 other protein kinases. Unlike Torin 1, Torin 2 inhibits the phosphatidylinositol-3 kinase–like kinase family members ATM, ATR, and DNA-PK. Investigators demonstrate that Torin 2 treatment of cells attenuates phosphorylation of mTOR downstream targets, inhibits cell proliferation of several cancer cell types, and induces apoptosis and autophagy. Indirect activation and nuclear translocation of TFEB through Torin 2 inhibition of mTORC1 has also been observed.

References

[1] liu q, wang j, kang s a, et al. discovery of 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl) phenyl) benzo [h][1, 6] naphthyridin-2 (1 h)-one (torin2) as a potent, selective, and orally available mammalian target of rapamycin (mtor) inhibitor for treatment of cancer. journal of medicinal chemistry, 2011, 54(5): 1473-1480.