ChemicalBook Product Catalog Biochemical Engineering Inhibitors PI3K / Akt / mTOR mTOR inhibitors XL-388

XL-388

Product NameXL-388
CAS1251156-08-7
MFC23H22FN3O4S
MW455.5
EINECS
MOL File1251156-08-7.mol

Chemical Properties

Melting point	>188oC (dec.)
Boiling point	738.6±60.0 °C(Predicted)
Density	1.354±0.06 g/cm3(Predicted)
storage temp.	Keep in dark place,Inert atmosphere,Store in freezer, under -20°C
solubility	DMSO (Slightly), Methanol (Slightly)
pka	6.22±0.13(Predicted)
form	Solid
color	Off-White to Pale Yellow
Stability	Hygroscopic
InChI	1S/C23H22FN3O4S/c1-14-18(5-7-20(22(14)24)32(2,29)30)23(28)27-9-10-31-19-6-3-15(11-17(19)13-27)16-4-8-21(25)26-12-16/h3-8,11-12H,9-10,13H2,1-2H3,(H2,25,26)
InChIKey	LNFBAYSBVQBKFR-UHFFFAOYSA-N
SMILES	Fc1c(ccc(c1C)C(=O)N2CCOc3c(cc(cc3)c4c[nH][c](cc4)=N)C2)[S](=O)(=O)C

Safety Information

WGK Germany	WGK 3
Storage Class	11 - Combustible Solids
Hazard Classifications	Eye Irrit. 2 Skin Irrit. 2 STOT SE 3

Usage And Synthesis

Uses

XL388 is a highly potent, orally bioavailable, selective, ATP-competitive mammalian target of rapamycin (mTOR) inhibitor. XL388 has shown significant and dose-dependent antitumor activity in athymic nude mice implanted with human tumor xenografts.

Biological Activity

XL388 is a potent, selective, orally bioavailable ATP-competitive inhibitor of mammalian target of rapamycin (mTOR) with an IC50 of 9.9 nM for mTOR, 8 nM for mTORC1, 166 nM for mTORC2, and 1000-fold selectivity for mTOR over the closely related PI3K kinases and a panel of 141 protein kinases tested. XL388 blocked mTORC1 phosphorylation of p70S6K (T389) with an IC50 value of 94 nM and blocked mTORC2 phosphorylationof AKT (S473) with an IC50 value of 350 nM. XL388 showed complete tumor growth inhibition in mice bearing MCF-7 xenograft tumors.

in vivo

To assess the pharmacodynamic effects of XL388 (Compound 28) on the mTOR pathway signaling, athymic nude mice bearing PC-3 prostate tumors are dosed orally at 100 mg/kg of XL388. Rapamycin is also administered intraperitoneally at 5 mg/kg as a reference. Plasma and tumor samples are collected at 1, 4, 8, 16, 24, and 32 h for XL388 and at 4 h for Rapamycin after dosing and homogenized with buffer. Tumor lysates from each animal (n=5) are then pooled for each group and analyzed by immunoblot for levels of phosphorylated p70S6K, S6, 4E-BP1, and AKT. XL388 has moderate terminal elimination half-life (t_1/2=1.35 h, 0.45 h, 6.11 h and 0.86 h for mouse (10 mg/kg, iv), rat (3 mg/kg, iv), dog (3 mg/kg, iv), monkey (3 mg/kg, iv))^[1].

IC 50

mTOR: 9.9 nM (IC₅₀); mTORC1; mTORC2; DNA-PK: 8.831 μM (IC₅₀)

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