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Biomarkers for determining effective response of treatments of hepatocellular carcinoma (HCC) patients

A biomarker, patient technology, applied in the direction of medical preparations containing active ingredients, amide active ingredients, biomaterial analysis, etc.

Inactive Publication Date: 2015-03-04
BAYER PHARMA AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] Despite the above-mentioned advances in cancer treatment, a major challenge in cancer treatment is selecting specific treatment options for patients based on genetic markers (i.e., biomarkers) to optimize treatment outcomes

Method used

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  • Biomarkers for determining effective response of treatments of hepatocellular carcinoma (HCC) patients
  • Biomarkers for determining effective response of treatments of hepatocellular carcinoma (HCC) patients
  • Biomarkers for determining effective response of treatments of hepatocellular carcinoma (HCC) patients

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0321] Example 1 : N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1-sulfonamide:

[0322] Step A: Butyl cyclopropanesulfonate :

[0323]

[0324] Cyclopropanesulfonyl chloride (5g, 35mmol, 1eq) was dissolved in excess BuOH (20ml), the reaction mixture was cooled at -10°C, and pyridine (5.8mL, 70mmol, 2eq) was slowly added dropwise. The mixture was slowly warmed to room temperature and stirred overnight. The solvent was removed under reduced pressure, and the resulting white solid was dissolved in CHCl 3 dissolved in. The organic phase was washed with water, brine, and dried (MgSO 4 ) and concentrated to give an oil (4.8 g, 24.9 mmol, 71%). 1 H NMR (300MHz, CDCl 3 ): δ4.25(t,2H),2.46(m,1H),1.74(m,2H),1.45(m,2H),1.25(dd,2H),1.09(dd,2H),.93(t ,3H).

[0325] Step B: Butyl 1-allylcyclopropane-1-sulfonate :

[0326]

[0327] To a solution of 1-butylcyclopropanesulfonate (4.8g, 24.9mmol) in THF was simultaneously added a ...

Embodiment 1A

[0340] Example 1A : (S)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2,3-dihydroxypropyl)cyclopropane-1- Sulfonamide:

[0341]

[0342] The pure S isomer was obtained by chiral HPLC separation of the racemic mixture (Example 13). 1 H NMR (300MHz, CDCl 3 +D 2 O): δ7.38(dd, J=1.8&10.5Hz, 1H), 7.36(ddd, J=2.4, 5.1&9.3Hz, 1H), 7.25(d, J=8.7Hz, 1H), 7.02(dd ,J=9.0&17.7Hz,1H),6.27(dt,J=3.0,8.7&17.4Hz,1H),3.92(m,1H),3.54(dd,J=3.9&11.1Hz,1H),3.39( dd, J=6.6&11.1Hz, 1H), 2.16(dd, J=9.6&15.9Hz, 1H), 1.59(d, J=14.1Hz, 1H), 1.41(m, 1H), 1.26(m, 1H ),0.83(m,2H); m / z=542[M-1] - .

Embodiment 1B

[0343] Example 1B : Example 1A: (R)-N-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)phenyl)-1-(2,3-dihydroxypropyl) ring Propane-1-sulfonamide:

[0344]

[0345]The pure R isomer was obtained by chiral HPLC separation of the racemic mixture (Example 13). 1 H NMR (300MHz, CDCl 3 +D 2 O): δ7.38(dd, J=1.8&10.5Hz, 1H), 7.36(ddd, J=2.4, 5.1&9.3Hz, 1H), 7.25(d, J=8.7Hz, 1H), 7.02(dd ,J=9.0&17.7Hz,1H),6.27(dt,J=3.0,8.7&17.4Hz,1H),3.92(m,1H),3.54(dd,J=3.9&11.1Hz,1H),3.39( dd, J=6.6&11.1Hz, 1H), 2.16(dd, J=9.6&15.9Hz, 1H), 1.59(d, J=14.1Hz, 1H), 1.41(m, 1H), 1.26(m, 1H ),0.83(m,2H); m / z=542[M-1] - .

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Abstract

This invention is directed to the use of one or more biomarkers defined as KRAS or NRAS gene for predicting the pharmaceutical efficacy or clinical response of MEK protein kinase inhibitor and / or Sorafenib or Regorafenib to be administred to a Hepatocellular carcinoma (HCC) patient. Futher the invention is directed to in-vitro methods for identifying mutated-type KRAS or NRAS gene in HCC patient and kits thereof.

Description

field of invention [0001] The present invention relates to one or more biomarkers defined as KRAS or NRAS genes for predicting the efficacy of MEK protein kinase inhibitors and / or sorafenib or regorafenib administered to patients with hepatocellular carcinoma (HCC) Use of pharmacological efficacy or clinical response. The present invention also relates to in vitro methods and kits for identifying mutant KRAS or NRAS genes in HCC patients. Background of the invention [0002] Oncogenes—genes that cause cancer—are usually mutated forms of certain normal cellular genes ("proto-oncogenes"). Oncogenes often encode abnormal forms of signaling pathway components such as receptor tyrosine kinases, serine-threonine kinases, or downstream signal transduction molecules. The major downstream signaling molecule is the Ras protein, which anchors on the inner surface of the plasma membrane and hydrolyzes bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When a growth fa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/00A61K31/18A61K31/44A61P35/00
CPCA61K31/18C12Q1/485G01N2800/52A61K31/44A61K2300/00A61K31/4412A61P1/16A61P35/00A61P43/00C12Q1/6886C12Q2600/106C12Q2600/156
Inventor H·克里塞尔F·普勒M·杰弗斯
Owner BAYER PHARMA AG