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Inhibitors of AKT activity

A technology of phenyl and naphthalene, which is applied in the direction of organic active ingredients, non-central analgesics, anti-inflammatory agents, etc., can solve the problem of no specific PDK1 inhibitor yet

Inactive Publication Date: 2013-10-16
SCHERING AG +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

No specific PDK1 inhibitors have been reported

Method used

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  • Inhibitors of AKT activity
  • Inhibitors of AKT activity
  • Inhibitors of AKT activity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0746] Cloning of human Akt isoforms and ΔPH-Akt1

[0747] The pS2neo vector (deposited at ATCC on April 3, 2001 with the accession number ATCCPTA-3253) was prepared as follows: cut the pRmHA3 vector with BglII (according to the method introduced in Nucl.AcidRes.16:1043-1061 (1988) Preparation), a 2734bp fragment was isolated. The pUChsneo vector (prepared according to the method described in EMBO J. 4: 167-171 (1985)) was also cut with BglII, and a 4029 bp fragment was isolated. The two isolated fragments were ligated to generate the vector, called pS2neo-1. This plasmid contains a polylinker between the metallothionein promoter and the alcohol dehydrogenase polyA addition site. It also has a neo resistance gene driven by a heat shock promoter. The pS2neo-1 vector was cut with Psp5II and BsiWI. Two complementary oligonucleotides were synthesized and then annealed (CTGCGGCCGC (SEQ. ID. NO.: 1) and GTACGCGGCCGCAG (SEQ. ID. NO.: 2)). The cut pS2neo-1 was ligated with the ...

Embodiment 2

[0763] Expression of human Akt isoforms and ΔPH-Akt1

[0764] Using the calcium phosphate method, the DNA containing the cloned Akt1, Akt2, Akt3 and ΔPH-Akt1 genes in the pS2neo expression vector was purified and transfected into Drosophila S2 cells (ATCC). Antibiotic (G418, 500 μg / ml) resistant cell aggregates were selected. Expand the cells to a volume of 1.0L (approximately 7.0×10 6 / ml), adding biotin and CuSO 4 , so that the final concentrations were 50μM and 50mM. Cells were grown for 72 hours at 27°C and harvested by centrifugation. The cell pellet (paste) was stored at -70°C and refrigerated until use.

Embodiment 3

[0766] Purification of human Akt isoforms and ΔPH-Akt1

[0767] The cell pellet obtained from 1 L of S2 cells described in Example 2 was dissolved in 50 ml of buffer A (50 mM Tris pH 7.4, 1 mM EDTA, 1 mM EGTA, 0.2 mM AEBSF, 10 μg / ml benzamidine) containing 1% CHAPS , 5 μg / ml each of leupeptin, aprotinin and pepstatin, 10% glycerol and 1 mM DTT), lysis was performed by sonication. The soluble fraction was purified with a protein G Sepharose (Sepharose) fast-flow (Pharmacia) column equipped with 9 mg / ml anti-intermediate T monoclonal antibody, and was purified with 75 μM EYMPME (SEQ.ID.NO.: 14) peptide in 25% Glycerol in Buffer A solution for elution. Fractions containing Akt / PKB were pooled and protein purity was assessed by SDS-PAGE. Purified proteins were quantified using standard Bradford protocols. Purified proteins were snap frozen in liquid nitrogen and stored at -70°C.

[0768] Requirement for activation of Akt and Akt platelet leukocyte C kinase substrate homology...

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Abstract

The present invention provides substituted naphthyridine compounds that inhibit the activity of Akt. In particular, the disclosed compounds selectively inhibit one or both Akt isozymes. The invention also provides compositions comprising such inhibitory compounds and methods of inhibiting Akt activity by administering said compounds to a patient in need of treatment for cancer.

Description

Background of the invention [0001] The present invention relates to substituted naphthyridine compounds which are inhibitors of the activity of one or more serine / threonine kinase Akt (also known as PKB; hereinafter "Akt") isozymes. The invention also relates to pharmaceutical compositions containing said compounds and methods of using the compounds of the invention in the treatment of cancer. [0002] Apoptosis (programmed cell death) plays a crucial role in embryonic development and in the pathogenesis of various diseases such as degenerative neuronal diseases, cardiovascular diseases and cancer. Recent studies have led to the identification of various pro-apoptotic and anti-apoptotic gene products involved in the regulation or execution of programmed cell death. Expression of anti-apoptotic genes, such as BC12 or BC 1 -x L The expression of various stimuli inhibits apoptotic cell death induced by various stimuli. On the other hand, expression of pro-apoptotic genes, suc...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04C07D401/06C07D403/04C07D403/06C07D407/04C07D409/04C07D413/04C07D417/04C07D471/14A61K31/4353A61P35/00
CPCC07D407/04C07D413/04C07D409/04C07D417/04C07D403/04C07D401/06C07D471/14C07D403/06C07D401/04A61P11/06A61P17/06A61P19/02A61P25/28A61P27/02A61P29/00A61P3/04A61P35/00A61P35/02A61P35/04A61P37/02A61P37/06A61P37/08A61P43/00A61P9/10A61P3/10C07D471/04A61K31/4353
Inventor M·J·凯利M·E·莱顿M·E·利括里Y·奥吉诺Y·奥诺扎基P·E·桑德森J·王
Owner SCHERING AG
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