Compositions and methods for inducing conformational changes in cereblon and other E3 ubiquitin ligases

Patent metadata

Field	Value
Publication number	US-11733233-B2
Application number	US-202016935097-A
Country	US
Kind code	B2
Filing date	Jul 21, 2020
Priority date	Dec 28, 2015
Publication date	Aug 22, 2023
Grant date	Aug 22, 2023

Abstract

Provided herein are compositions, therapeutic methods, screening methods, computational methods and biomarkers based upon the elucidation of the interaction among cereblon, its substrates and certain compounds or agents, including small molecules, peptides, and proteins.

First claim

What is claimed is:

1. A complex comprising a cereblon (CRBN), a treatment compound, and a cereblon-associated protein (CAP) wherein the CAP comprises a degron of [D/N]XX[S/T]G (SEQ ID NO:1), CXXCG (SEQ ID NO: 6), or NXXNG (SEQ ID NO: 7), wherein X can be any amino acid, wherein the CAP is not IKZF1, wherein the treatment compound is a synthesized small molecule compound.

2. The complex of claim 1 , wherein the structural degron comprises an α-turn.

3. The complex of claim 1 , wherein the degron comprises 5 amino acid residues, with positions designated as i−1, i, i−1, i+2, and i+3, respectively.

4. The complex of claim 3 , wherein the amino acid residues at position i, i+1, or i+2 form hydrogen bonds with amino acid residues on CRBN.

5. The complex of claim 3 , wherein the amino acid residues at position i, i+1, and i+2 form hydrogen bonds with amino acid residues on CRBN.

6. The complex of claim 1 , wherein the degron of SEQ ID NO: 1 is stabilized by internal hydrogen bonds from an ASX motif and a ST motif.

7. The complex of claim 1 , wherein the degron comprises an ASX motif that starts with Asparagine (N).

8. The complex of claim 1 , wherein the degron comprises an ST motif that starts with Serine (S).

9. The complex of claim 1 , wherein the degron comprises a ST motif that starts with Threonine (T).

10. The complex of claim 1 , wherein the degron comprises an amino acid sequence of [D/N]XX[S/T]G (SEQ ID NO:1), wherein X can be any amino acid.

11. The complex of claim 1 , wherein the degron comprises an amino acid sequence of CXXCG (SEQ ID NO:6), wherein X can be any amino acid.

12. The complex of claim 1 , wherein the degron comprises an amino acid sequence of NXXNG (SEQ ID NO:7), wherein X can be any amino acid.

13. The complex of claim 1 , wherein the CAP is a substrate of CRBN, and wherein the substrate is GSPT1.

14. The complex of claim 1 , wherein the CAP is a substrate of CRBN, wherein the substrate is CK1a.

15. The complex of claim 1 , wherein the treatment compound is a cereblon modifying agent (CMA).

16. The complex of claim 1 , wherein the treatment compound is an immunomodulatory compound.

17. The complex of claim 1 , wherein the treatment compound is selected from the group consisting of thalidomide, lenalidomide, pomalidomide, Compound A (3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione), Compound B (3-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)piperidine-2,6-dione), Compound C (1-(3-chloro-4-methylphenyl)-3-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)urea), Compound D (2-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide), and Compound E (2-(4-flurophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2,2-difluoroacetamide).

Assignees

• Celgene Corp

Inventors

• Cathers Brian E
• Chamberlain Philip
• Lopez-Girona Antonia
• Lu Gang

Classifications

• G01N33/5008 Primary

  for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics · CPC title

• A61K31/4035 Primary

  Isoindoles, e.g. phthalimide · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07K14/4702

  Regulators; Modulating activity · CPC title