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).
Claims47
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 CRBN in the presence of argininosuccinate synthetase 1 (ASS1);
- (c) assaying for direct or indirect recruitment and/or ubiquitination and/or degradation of ASS1;
- and
- (d) classifying the test compound as a candidate compound if reduced, low or substantially no direct or indirect recruitment and/or ubiquitination and/or degradation of ASS1 is detected.
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 CRBN in the presence of argininosuccinate synthetase 1 (ASS1);
- (iii) assaying for direct or indirect recruitment and/or ubiquitination and/or degradation of ASS1;
- and
- (iv) classifying the test compound as a candidate compound if reduced, low or substantially no direct or indirect recruitment and/or ubiquitination and/or degradation of ASS1 is detected;
- and
- (b) formulating the candidate compound for use in a therapy.
The method of any one of the above claims, wherein the test compound or candidate compound binds CRBN but weakly binds to, or does not substantially bind, ASS1.
The method of any one of the above claims, wherein the test compound or candidate compound binds CRBN with an affinity of about 1 μM, or higher.
The method of any one of the above claims, wherein the test compound or candidate compound is a molecular glue.
The method of any one of the above claims, wherein the test compound or candidate compound comprises a glutarimide ring and a phthalimide ring.
The method of any one of the above claims, wherein the test compound or candidate compound induces exposure of a hydrophobic surface of CRBN that allows for interaction with a substrate and/or neosubstrate of CRBN that is not ASS1.
The method of any one of the above claims, wherein the test compound or candidate compound is an immunomodulatory drug or an immunomodulatory imide drug (IMiD), or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
The method of any one of the above claims, wherein the degradation is ubiquitin-dependent.
The method of any one of the above claims, wherein the candidate compound is suitable for use in treating a cancer, optionally selected from a hematologic malignancy, further optionally selected from multiple myeloma and 5q-deletion-associated myelodysplastic syndrome (del(5q) MDS).
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 CRBN in the presence of argininosuccinate synthetase 1 (ASS1);
- (c) assaying a direct or indirect recruitment and/or ubiquitination and/or degradation of ASS1;
- and
- (d) classifying the test compound as a candidate compound if high or increased direct or indirect recruitment and/or ubiquitination and/or degradation of ASS1 is detected.
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 CRBN in the presence of argininosuccinate synthetase 1 (ASS1);
- (iii) assaying for direct or indirect recruitment and/or ubiquitination and/or degradation of ASS1;
- and
- (iv) classifying the test compound as a candidate compound if high or increased direct or indirect recruitment and/or ubiquitination and/or degradation of ASS1 is detected;
- and
- (b) formulating the candidate compound for use in a therapy.
The method of any of the above claims, wherein the candidate compound is a therapeutic compound.
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 CRBN in the presence of argininosuccinate synthetase 1 (ASS1);
- (c) assaying for direct or indirect recruitment and/or ubiquitination and/or degradation of ASS1;
- and
- (d) classifying the test compound as a candidate compound if reduced, low or substantially no direct or indirect recruitment and/or ubiquitination 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 and/or ubiquitination 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.
Dependencies are inferred from the claim text.