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US 12,546,776 B2Granted
Modulation of protein degradation
AssigneeOrionis Biosciences BV
InventorsNikolai Kley, Samuel Lievens, Riccardo Sabatini
Life of this patent
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Abstract
Methods of assessing the efficacy of an agent in treating a disease or disorder are provided that include determining whether the agent causes, or inhibits, direct or indirect recruitment and/or ubiquitination and/or degradation of argininosuccinate synthetase 1 (ASS1).
Claims20
A method for identifying a candidate compound, comprising:
- (a) obtaining a test compound having the ability to bind to cereblon (CRBN);
- (b) contacting the test compound with cells expressing CRBN, the contacting being in the presence of argininosuccinate synthetase 1 (ASS1);
- (c) assaying for direct or indirect recruitment of ASS1 and/or ubiquitination of ASS1 and/or degradation of ASS1 after step (b);
- and
- (d) classifying the test compound as a candidate compound if reduced, low or substantially no direct or indirect recruitment of ASS1 and/or ubiquitination of ASS1 and/or degradation of ASS1 is detected.
2 more elements
A method for making a therapeutic composition, comprising:
- (a) identifying a candidate compound by:
- (i) obtaining a test compound having the ability to bind to cereblon (CRBN);
- (ii) contacting the test compound with cells expressing CRBN, the contacting being in the presence of argininosuccinate synthetase 1 (ASS1);
- (iii) assaying for direct or indirect recruitment of ASS1 and/or ubiquitination of ASS1 and/or degradation of ASS1 after step (ii);
- and
- (iv) classifying the test compound as a candidate compound if reduced, low or substantially no direct or indirect recruitment of ASS1 and/or ubiquitination of ASS1 and/or degradation of ASS1 is detected;
- and
- (b) formulating the candidate compound for use in a therapy.
5 more elements
A method for identifying a candidate compound, comprising:
- (a) obtaining a test compound having the ability to bind to cereblon (CRBN);
- (b) contacting the test compound with cells expressing CRBN, the contacting being in the presence of argininosuccinate synthetase 1 (ASS1);
- (c) assaying for direct or indirect recruitment of ASS1 and/or ubiquitination of ASS1 and/or degradation of ASS1 after step (b);
- and
- (d) classifying the test compound as a candidate compound if reduced, low or substantially no direct or indirect recruitment of ASS1 and/or ubiquitination of ASS1 and/or degradation of ASS1 is detected,
- further comprising assaying for direct or indirect recruitment and/or ubiquitination and/or degradation of a substrate and/or neosubstrate of CRBN that is not ASS1, the substrate and/or neosubstrate of CRBN that is not ASS1 is selected from Ikaros (IKZF1), Helios (IKZF2), Aiolos (IKZF3), Eos (IKZF4), Pegasus (IKZF5), CSNK1A, CK1a, and ZFP91, and
- wherein the classifying is based on the test compound's ability to shift a ratio of direct or indirect recruitment of ASS1 and/or ubiquitination of ASS1 and/or degradation of ASS1 relative to direct or indirect recruitment and/or, ubiquitination and/or degradation of the substrate and/or neosubstrate of CRBN that is not ASS1.
4 more elements
Dependencies are inferred from the claim text.