Molecular Weight (MW)

512.53

Formula

C28H25FN6O3

CAS No.

603288-22-8

Storage

-20℃ for 3 years in powder form

-80℃ for 2 years in solvent

Solubility (In vitro)

DMSO: 100 mg/mL (195.1 mM)

Water: <1 mg/mL

Ethanol: 2 mg/mL warmed (3.9 mM)

SMILES

O=C(C(C1=CN2C3=C1C=C(F)C=C3CN(C(N4CCCCC4)=O)CC2)=C5C6=CN=C7C=CC=CN76)NC5=O

Synonyms

LY 2090314; LY2090314; LY-2090314

Chemical Name: 3-(9-fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-(imidazo[1,2-a]pyridin-3-yl)-1H-pyrrole-2,5-dione

InChi Key: HRJWTAWVFDCTGO-UHFFFAOYSA-N

InChi Code: InChI=1S/C28H25FN6O3/c29-18-12-17-15-34(28(38)32-7-3-1-4-8-32)11-10-33-16-20(19(13-18)25(17)33)23-24(27(37)31-26(23)36)21-14-30-22-6-2-5-9-35(21)22/h2,5-6,9,12-14,16H,1,3-4,7-8,10-11,15H2,(H,31,36,37)

In Vitro

In vitro activity: LY2090314 selectively inhibits the activity of GSK-3 by interrupting ATP binding. LY2090314 is able to stabilize β-catenin. LY2090314 shows limited efficacy as monotherapy. LY3090314 enhances the efficacy of cisplatin and carboplatin in solid tumor cancer cell lines in vitro.

Kinase Assay: LY2090314 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) with IC50 values of 1.5 nM and 0.9 nM for GSK-3α and GSK-3β, respectively.

Cell Assay: LY2090314 (20 nM) promotes a time-dependent stabilization of β-catenin total protein as well as an induction of Axin2. LY2090314 is highly selective towards GSK3 as demonstrated by its fold selectivity relative to a large panel of kinases. LY2090314 potently induces apoptotic cell death in a panel of melanoma cell lines irrespective of BRAF mutation status. Cell death induced by LY2090314 is dependent on β-catenin and GSK3β knockdown increases the sensitivity of cells to LY2090314. LY2090314 remains active in cell lines resistant to Vemurafenib and has an independent mechanism of action.

In Vivo

LY2090314 enhances the efficacy of cisplatin and carboplatin in solid tumor cancer xenografts

Animal model

Athymic nude mice:Five million A375 human melanoma cancer cells are injected S.C. in the flank of female 6 to 8 week old athymic nude mice in a 1:1 mixture with matrigel. Mice are monitored daily for palpable tumors. When tumors reach appr 100 mm2 mice are randomized into groups receiving either LY2090314 (25 mg/kg Q3D) or vehicle (20% Captisol/0.01N HCl) via i.v. administration. Tumor volume (measured by calipers) and animal body weight are recorded twice weekly. Tumor volumes are calculated using the formula: (a2 × b)/2 (a being the smaller and b being the larger dimension of the tumor). For combination studies with DTIC (60 mg/kg QD), LY2090314 is dosed at 2.5 mg/kg Q3D and tumor growth monitored.

Formulation & Dosage

LY2090314 (25 mg/kg Q3D) or vehicle (dissolved in 20% Captisol/0.01N HCl) via i.v. administration.

References

[1] Brail LH, et al. J Clin Oncol, 2011, 29, abstr 3030.