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US 2025/0066864 A1Published application
Methods for identifying adar1 inhibitors, and compositions and methods of use in treating cancer
OwnerKazuko Nishikurainventor
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Abstract
Provided herein are methods of screening for ADAR1 inhibitors, and compounds identified by the method. In certain embodiments, the methods include treating with an inhibitor of ADAR1.
Claims21
A screening method comprising:
- a) providing a test compound to a non-ALT cancer cell comprising a nucleic acid that comprises a dual reporter system, said dual reporter system comprising i) a first reporter, ii) an adenosine-to-inosine (A-to-I) editing site within a stop codon of a short hairpin dsRNA, and iii) a second reporter, wherein the first reporter and second reporter are different, and wherein adenosine to inosine editing alters the stop codon to Trp, resulting in in-frame translation of the second reporter,
- b) measuring the levels of expression of the first reporter and the second reporter;
- wherein the ratio of the expression level of the second reporter to the ratio of the expression level of the first reporter demonstrates A-to-I editing efficiency;
- wherein the test compound is an inhibitor of ADAR1 when the editing efficiency is decreased at least 60% as compared to a control.
1 more element
(canceled)
A composition comprising:
- a cancer cell comprising a nucleic acid that comprises a dual reporter system, said dual reporter system comprising i) a first reporter, ii) an adenosine-to-inosine (A-to-I) editing site within a stop codon of a short hairpin dsRNA, and iii) a second reporter, wherein the first reporter and second reporter are different.
A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more of:
- a) [[amino-[3-chloro-4-[(4-chlorophenyl)methoxy]phenyl]methylidene]amino]5-nitrofuran-2-carboxylate
- b) 5,7-dimethyl-2-phenylpyrazolo[1,5-a]pyrimidine
- c) 3-chloro-N-(4-cyanophenyl)-1-benzothiophene-2-carboxamide
- d) 1-[(4-chlorophenyl)methylsulfanyl]-3-phenylpyrido[1,2-a]benzimidazole-4-carbonitrile
- e) N-(1-benzylpiperidin-4-yl)-6-phenylthieno[3,2-d]pyrimidin-4-amine
- f) 5-(4-chlorophenyl)-3-methylsulfanyl-1H-pyrazole-4-carbonitrile
- g) 4-[6-(3,5-dimethylpyrazol-1-yl)pyridazin-3-yl]thiomorpholine
- h) 3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyridazin-6-one;
- i) 4-(furan-2-yl)-2,6-bis(methylsulfanyl)pyrimidine-5-carbonitrile,
- or a prodrug, derivative, pharmaceutical salt, or analog thereof.
7 more elements
21-24. (canceled)
Dependencies are inferred from the claim text.