Small-molecule-targeted protein degradation

Patent metadata

Field	Value
Publication number	US-9765019-B2
Application number	US-201113805508-A
Country	US
Kind code	B2
Filing date	Jun 30, 2011
Priority date	Jun 30, 2010
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

Certain aspects of the invention relate to compounds, compositions and methods that are useful for treating or preventing a disease in a subject by enhancing the degradation of a protein. In other aspects, said compounds can be useful research tools for investigating protein degradation. In other aspects, said compounds are useful research tools for investigating protein function. In certain embodiments, the degraded protein is implicated in a disease or disorder whose pathology is related at least in part to the excessive expression of the protein or the expression of a mutant form of the protein.

First claim

We claim:

1. A compound, comprising:
a protein-binding moiety which binds a protein,
a tag which promotes the degradation of said protein, and
a covalent linker which connects the protein-binding moiety to the tag;
wherein
the protein binding moiety is selected from the group consisting of

X is —(CH 2 ) n —;
Y is chloro, bromo, or iodo;
the covalent linker is —N(H)[CH 2 ] n N(H)—, —(OCH 2 CH 2 ) n O—, or —(OCH 2 CH 2 ) n NH—;
n is independently 1-10 inclusive;
the tag is

R 1 , R 2 , and R 3 are tert-butoxycarbonyl.

2. The compound of claim 1 , wherein the protein is selected from the group consisting of glutathione-S-transferase α1 (GST), dihydrofolate reductase (DHFR), botulinum toxin (BoNT), Bcr-Abl, thioredoxin interacting protein (TXNIP), mutant forms of Ras that cause cancer, and mutant forms of IMP dehydrogenase type 1 (IMPDH1) that cause retinitis pigmentosa.

3. The compound of claim 1 , wherein the protein is a fusion protein comprising a first protein and a second protein; the protein-binding moiety binds the first protein; and the tag promotes the degradation of the second protein.

4. The compound of claim 3 , wherein the first protein is GST, DHFR, SNAP, CLIP, or HALO.

5. The compound of claim 1 , wherein the compound is represented by formula I, or a pharmaceutically acceptable salt thereof,

6. The compound of claim 1 , wherein the compound is represented by formula II, or a pharmaceutically acceptable salt thereof,

7. A compound represented by formula III, or a pharmaceutically acceptable salt thereof,

wherein X is —(CH 2 ) n —;
n is 1-10 inclusive;
R 1 , R 2 , and R 3 are tert-butoxycarbonyl.

8. The compound of claim 1 , wherein the compound is represented by formula IV, or a pharmaceutically acceptable salt thereof,

9. A compound represented by formula VI, or a pharmaceutically acceptable salt thereof,

wherein X is —(CH 2 ) n —;
n is 1-10 inclusive;
R 1 , R 2 , and R 3 are tert-butoxycarbonyl.

10. A composition, comprising a compound of claim 1 ; and a pharmaceutically acceptable excipient.

11. A compound-represented by formula IIa, or a pharmaceutically acceptable salt thereof,

wherein
X is —N(H)[CH 2 ] n N(H)—;
n is 1-10;
R 1 is tert-butoxycarbonyl;
R 2 is tert-butoxycarbonyl, or p-toluenesulfonyl; and
R 3 is tert-butoxycarbonyl or hydrogen.

12. A composition, comprising a compound of claim 11 ; and a pharmaceutically acceptable excipient.

Assignees

• Hedstrom Lizbeth K
• Long Marcus
• Gollapalli Deviprasad R
• Univ Brandeis

Inventors

• Hedstrom Lizbeth K
• Long Marcus
• Gollapalli Deviprasad R

Classifications

• A61K47/48038

  Human Necessities · mapped topic

• C07C65/40

  containing singly bound oxygen-containing groups · CPC title

• A61K47/48061

  Human Necessities · mapped topic

• A61K31/4184 Primary

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• C07C211/12

  1,6-Diaminohexanes · CPC title