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Inhibitors of ataxia-telangiectasia mutated and rad3-related protein kinase (ATR) for use in methods of treating cancer

A technology of protein kinase inhibitors and telangiectasia, applied in the treatment of BAF complex gene mutation or defective cancer, using synthetic lethal materials to treat cancer, can solve problems such as drug treatment differences

Pending Publication Date: 2018-12-21
THE INST OF CANCER RES ROYAL CANCER HOSPITAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

A consequence of this molecular heterogeneity is that individuals often exhibit large differences in response to drug therapy

Method used

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  • Inhibitors of ataxia-telangiectasia mutated and rad3-related protein kinase (ATR) for use in methods of treating cancer
  • Inhibitors of ataxia-telangiectasia mutated and rad3-related protein kinase (ATR) for use in methods of treating cancer
  • Inhibitors of ataxia-telangiectasia mutated and rad3-related protein kinase (ATR) for use in methods of treating cancer

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0343] method

[0344] cell culture

[0345] ES2 and TOV21G were obtained from the American Type Tissue Collection. RMG-1, SMOV2, KOC7C, HCH1, OVAS, OVISE, OVMANA, OVTOKO, OVSAYO and KK were kindly provided by Dr. Hiroaki Itamochi (Tottori University School of Medicine, Yonago, Japan). Ovarian clear cell carcinoma lines were grown in McCoys with 10% FCS. The identity of the cell lines was confirmed in March 2013 by short direct repeat (STR) typing using the StemElite kit (Promega). The ARID1A HCT116 isogenic cell line was obtained from Horizon Discovery and grown in McCoys with 10% FCS. Arid1a null and wild-type mouse embryonic stem cells were obtained from Dr. Zhong Wang (Harvard Medical School, USA) and grown on gelatin-coated plates in DMEM with 10% FCS supplemented with 0.1 mM NEAA, 1 mM pyruvate Sodium, 0.1 mM β-mercaptoethanol and 2000 U LIF / ml.

[0346] VE-821 siRNA Screening

[0347] siRNA library was purchased from Dharmacon. Genes were selected as described in...

Embodiment 2

[0387]A more recently used approach to identify therapeutic targets in cancer is to identify and exploit genetic dependencies, such as synthetic lethal and gene-addictive effects, that are associated with defects in specific cancer driver genes. For example, the synthetic lethal interaction between BRCA1 or BRCA2 tumor suppressor genes and small molecule PARP inhibitors provides a rationale for the use of PARP inhibitors in the treatment of BRCA1 / 2 mutant ovarian and prostate cancers (Lord, Tutt et al. 2015, Mateo, Carreira et al. 2015). This specific synthetic lethal interaction targets defective tumor suppressor genes by inhibiting PARP1, a component of the DNA damage response (DDR) molecular network. In human cells, as in lower organisms, DDR consists of a series of overlapping mechanisms that maintain genome integrity in the face of DNA damage (Lord and Ashworth 2016). One of the key elements in several conserved DDR pathways is the kinase ATR (ataxia telangiectasia and R...

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Abstract

The present invention relates to Ataxia-Telangiectasia Mutated and Rad3-related protein kinase (ATR) inhibitors for use in methods of treating BAF-complex deficient cancer. The present invention further provides methods for identifying ATR inhibitors for use in the treatment of BAF complex gene mutant or deficient cancers. Medical uses and methods relating to the treatment of synovial sarcoma using ATR inhibitors are also provided.

Description

field of invention [0001] The present invention relates to ataxia-telangiectasia mutated and Rad3-related protein kinase (ATR) inhibitors for use in methods of treating BAF-complex-deficient cancers, and in particular to the use of synthetic lethal (e.g. using ATR inhibitors) materials and methods for treating cancer, such as ARID1A-deficient cancer. The present invention also provides methods of identifying ATR inhibitors for use in the treatment of BAF complex gene mutant or deficient cancers. Also provided are medical uses and methods related to the use of ATR inhibitors for the treatment of synovial sarcoma. Background of the invention [0002] Each year, most new cancer drug approvals are for existing targets, while only two or three compounds are licensed for novel molecules. This reflects the difficulty, time and cost involved in identifying and validating proteins critical to disease pathogenesis, rather than suggesting a limited number of targets. The result is t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4965A61K31/497A61P35/00
CPCA61K31/4965A61K31/497A61P35/00A61K31/519A61K31/7105
Inventor 克勒斯托弗·詹姆斯·洛德C·威廉森S·琼斯
Owner THE INST OF CANCER RES ROYAL CANCER HOSPITAL
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