603288-22-8

Usage

Uses

Used in Pharmaceutical Industry:
LY2090314 is used as a therapeutic agent for the treatment of acute myeloid leukemia (AML). It targets the GSK-3α enzyme, which is involved in the regulation of cell growth and differentiation. In AML, the inhibition of GSK-3α by LY2090314 can help control the uncontrolled proliferation of leukemia cells and potentially lead to the remission of the disease.
Additionally, due to its mechanism of action, LY2090314 may also have potential applications in other cancer types or conditions where GSK-3α plays a significant role. However, further research and clinical trials would be necessary to establish its efficacy and safety in these contexts.

Biological Activity

ly2090314 (ly) is a potent inhibitor of glycogen synthase kinase-3 (gsk-3) which plays an important role in various pathways, such as protein synthesis initiation, cell proliferation/differentiation, and apoptosis.

Biochem/physiol Actions

LY2090314 is a potent and selective ATP-competitive inhibitor of Glycogen synthase kinase-3 (GSK-3) currently in clinical trials for cancer therapy. LY2090314 has IC50 values of 1.5 nM and 0.9 nM for GSK-3α and GSK-3β, respectively.

in vitro

ly2090314 selectively inhibits the activity of gsk-3 by inhibiting atp binding. ly2090314 was reported to be able to stabilize β-catenin. as monotherapy, ly2090314 aslso showed limited efficacy. in solid tumor cancer cell lines, ly3090314 was found to enhance the efficacy of cisplatin and carboplatin [1].

in vivo

even in mdr1a-, bcrp-, and mrp2-knockout rats, the metabolites of ly2090314 did not appear in systemic circulation, and the urinary excretion was not found to be enhanced, since the hypothesized impaired biliary excretion of metabolites in the absence of these canalicular transporters was not observed. dog metabolite disposition was similar, with the exception of ly2090314 glucuronide. moreover, ly2090314 enhances the efficacy of cisplatin and carboplatin in solid tumor cancer xenografts [1]

IC 50

1.5 nm (gsk-3α); 0.9 nm (gsk-3β)

references

[1] brail lh, et al. j clin oncol, 2011, 29, abstr 3030.

Upstream product

• 13939-69-0 piperidine carbamoyl chloride 
• 603272-51-1 3-(9-fluoro-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-4-imidazo[1,2-a]pyridin-3-yl-pyrrole-2,5-dione hydrochloride 
• 21801-86-5 2-(imidazo-[1,2-a]pyridin-3-yl)acetamide 
• 603300-92-1 9-fluoro-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid tert-butyl ester 
• 722539-12-0 methanesulfonic acid 2-[tert-butoxybarbonyl-(5-fluoro-1H-indol-7-ylmethyl)-amino]-ethyl ester 
• 603301-25-3 7-methoxyoxalyl-9-fluoro-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid tert-butyl ester 
• 1239017-87-8 methyl 2-(9-fluoro-2-(piperidine-1-carbonyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-2-oxoacetate 
• 722539-10-8 2-[(5-fluoro-1H-indol-7-ylmethyl)-amino]-ethanol 
• 504-29-0 2-aminopyridine 
• 1027312-01-1 9-fluoro-7-(4-imidazo[1,2-a]pyridin-3-yl-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl)-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carboxylic acid tert-butyl ester 
• 722539-11-9 (5-fluoro-1H-indol-7-ylmethyl)-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester 
• 603306-58-7 2-(dibutoxymethyl)-4-fluoro-1-nitrobenzene 
• 603306-52-1 5-fluoro-1H-indole-7-carbaldehyde 
• 287121-32-8 (5-Fluoro-2-nitrophenyl)-methanol 

Relevant academic research and scientific papers

Pictet-Spengler based synthesis of a bisarylmaleimide glycogen synthase kinase-3 inhibitor

A practical synthesis of the glycogen synthase kinase-3 (GSK3) inhibitor bisarylmaleimide 1 has been accomplished employing Pictet-Spengler methodology to access the indole 7-position in preparing the benzodiazepine tricyclic fragment. A seven-step linear sequence that starts with commercially available 5-fluoroindole 7 affords the bisarylmaleimide 1 in 33% overall yield.

POTENTIATION OF CANCER CHEMOTHERAPY

An improved method for treating gastric cancer, ovarian cancer, non-small cell lung cancer, or colorectal cancer in a patient is described, as well as pharmaceutical compositions useful for the method and a process for preparing said compositions.

HEMATOPOIETIC NEOPLASM CHEMOTHERAPY

A method and medicament for treating mixed lineage leukemia; translocated mixed lineage leukemia; translocated mixed lineage leukemia based acute myelogenous leukemia; translocated mixed lineage leukemia based acute lymphoid leukemia; a non-MLL based chronic myeloproliferative disorder, or non-MLL based acute lymphoid leukemia is provided.

Substituted 3-imidazo[1,2-a]pyridin-3-yl-4-(1,2,3,4-tetrahydro-[1,4] diazepino-[6,7,1-hi]indol-7-yl)pyrrole-2,5-diones as highly selective and potent inhibitors of glycogen synthase kinase-3

Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7-12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.