Granted Patent B2

US 12,383,624 · App. 18/169,734 · Granted Aug 12, 2025

Inventors: Yong Tae Kwon (Seoul, KR); Chang Hoon Ji (Seoul, KR); Srinivasrao Ganipisetti (Seoul, KR); Hee Yeon Kim (Seoul, KR); Su Ran Mun (Seoul, KR); Chan Hoon Jung (Seoul, KR); Eui Jung Jung (Seoul, KR); Ki Woon Sung (Seoul, KR); Hyun Tae Kim (Seoul, KR); Jeong Eun Na (Seoul, KR); Eun Hye Jeong (Seoul, KR); Ji Eun Lee (Seoul, KR); Min Ju Lee (Seoul, KR); Chang Min Park (Seoul, KR); Su Jin Kim (Seoul, KR)

Assignees: SEOUL NATIONAL UNIVERSITY R&DB FOUNDATION; AUTOTAC INC.

A61K47/545A61K47/55

Abstract

Claims (181)

1. A cargo delivery system, comprising

an autophagy targeting ligand; and

a target-binding ligand, which is cargo, carried by the autophagy targeting ligand,

wherein the autophagy targeting ligand is connected to the target-binding ligand by a linker,

wherein the autophagy targeting ligand connected to the target-binding ligand by a linker is selected from the group consisting of compounds shown in the following table:

No.

Name of Compound

 1

(2E,4E,6E,8E)-N-(2-(2-(2-(((R)-3-(3,4-bis

(benzyloxy)phenoxy)-2-hydroxypropyl)amino)

ethoxy)ethoxy)ethyl)-3,7-dimethyl-9-(2,6,6-

trimethylcyclohex-1-en-1-yl)nona-2,4,6,8-

tetraenamide

 2

(2E,4E,6E,8E)-N-(2-(2-(2-((3,4-bis(benzyloxy)

benzyl)amino)ethoxy)ethoxy)ethyl)-3,7-

dimethyl-9-(2,6,6-trimethylcyclohex-1-en-1-yl)

nona-2,4,6,8-tetraenamide

 3

(R)-N-(15-(3,4-bis(benzyloxy)phenoxy)-14-

hydroxy-3,6,9-trioxa-12-azapentadecyl)-4-

phenylbutaneamide

 4

N-(1-(3,4-bis(benzyloxy)phenyl)-5,8,11-trioxa-

2-azatridecan-13-yl)-4-phenylbutanamide

 5

3-(3-(benzo[d][1,3]dioxol-5-yl)-1H-pyrazol-

5-yl)-N-(2-(2-(2-((3-((4-fluorobenzyl)oxy))

benzyl)amino)ethoxy)ethoxy)ethyl)aniline

 6

(3R,4S,5S,6R)-5-methoxy-4-((2R,3R)-2-

methyl-3-(3-methylbut-2-en-1-yl)oxirane-2-yl)-

1-oxaspiro[2.5]octan-6-yl(13E,15E,17E,19E)-1-

(3-(benzyloxy)phenyl)-12-oxo-5,8-dioxa-2,11-

diazahenicosa-13,15,17,19-tetraene-21-oate

 7

3-(3,5-dichlorophenyl)-5-((R)-15-(3,4-

diphenethoxyphenoxy)-14-hydroxy-6,9-dioxa-

3,12-diazapentadecyl)-5-methyloxazolidine-

2,4-dione

 8

(R)-1-(4-(benzyloxy)-3-(3-phenylpropoxy)

phenoxy)-3-((2-(2-(2-(4-(2-phenyl-5,7-bis

(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-

3-yl)phenoxy)ethoxy)ethoxy)ethyl)amino)

propan-2-ol

 9

(R,Z)-4-((2-(2-(2-((3-(3,4-diphenethoxyphenoxy)-

2-hydroxypropyl)amino)ethoxy)ethoxy)ethyl)

imino)-2-phenyl-4H-chromene-5,6,7-triol

10

(E)-5-(4-(2-(2-(2-((3,4-bis(benzyloxy)benzyl)

amino)ethoxy)ethoxy)ethoxy)styryl)benzene-

1,3-diol

11

(R)-2-(4-(benzo[d]thiazol-2-yl)phenyl)-14-(3,4-

bis(benzyloxy)phenoxy)-5,8-dioxa-2,11-

diazatetradecane-13-ol

12

(1E,6E)-1-(4-(2-(2-(2-(((R)-3-(3-(benzyloxy)-

4-phenethoxyphenoxy)-2-hydroxypropyl)

amino)ethoxy)ethoxy)ethoxy)-3-methoxyphenyl)-

7-(4-hydroxy-3-methoxyphenyl)hepta-

1,6-diene-3,5-dione

13

(R)-1-(3-phenethoxyphenoxy)-3-((2-(2-(2-((6-

(trifluoromethoxy))benzo[d]thiazol-2-yl)amino)

ethoxy)ethoxy)ethyl)amino)propan-2-ol

14

N-(2-(2-(2-(((R)-3-(3,4-bis(benzyloxy)phenoxy)-

2-hydroxypropyl)amino)ethoxy)ethoxy)

ethyl)-2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-

6H-thieno[3,2-f][1,2,4]triazolo[4,3-a]

[1,4]diazepin-6-yl)acetamide

15

(1s, 4s)-N-(2-(2-(2-((3,4-bis(benzyloxy)benzyl)

amino)ethoxy)ethoxy)ethyl)-4-cyano-4-(3-

(cyclopentyloxy)-4-methoxyphenyl)cyclohexane-

1-carboxamide

16

(R)-1-(3-phenethoxyphenoxy)-3-((2-(2-(2-(4-(4-

(3-(quinolin-5-yl)pyrazolo[1,5-a]pyrimidin-6-

yl)phenyl)piperazin-1-yl)ethoxy)ethoxy)ethyl)

amino)propan-2-ol

17

5-(3-fluorophenyl)-N-((S)-1-(2-(2-(2-(((R)-2-

hydroxy-3-(3-phenethoxyphenoxy)propyl)

amino)ethoxy)ethoxy)ethyl)piperidin-3-yl)-

3-ureidothiophene-2-carboxamide

18

(R)-2-((6-(4-(15-(4-(benzyloxy)-3-(3-

phenylpropoxy)phenoxy)-14-hydroxy-6,9-dioxa-

3,12-diazapentadecyl)piperazin-1-yl)-2-

methylpyrimidin-4-yl)amino)-N-(2-chloro-6-

methylphenyl)thiazole-5-carboxamide

19

(R)-5-((3-((2-(2-(2-((3-(4-(benzyloxy)-3-

phenethoxyphenoxy)-2-hydroxypropyl)amino)

ethoxy)ethoxy)ethyl)amino)phenyl)amino)

benzo[c][2,6]naphthyridine-8-carboxylic acid

20

N-(7-((1-(3-(benzyloxy)phenyl)-5,8-dioxa-

2,11-diazatridecan-13-yl)oxy)-6-(tert-butylsulfonyl)

quinazolin-4-yl)benzo[d]thiazol-5-amine

21

((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-

(benzhydrylamino)-1,5-dioxopentan-2-

yl)carbamoyl)-3-((R)-1-(3,4-bis((4-fluorobenzyl)

oxy)phenoxy)-2-hydroxy-7,10,13,16-tetraoxa-

4-azaicosan-20-oyl)-6-oxodecahydropyrrolo

[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5-

yl)difluoromethyl)phosphonic acid

22

((2-(((5S,8S,10aR)-8-(((S)-5-amino-1-

(benzhydrylamino)-1,5-dioxopentan-2-yl)

carbamoyl)-3-(1-(3,4-bis(benzyloxy)phenyl)-

5,8,11,14-tetraoxa-2-azaoctadecan-18-oyl)-6-

oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-

yl)carbamoyl)-1H-indol-5-yl)difluoromethyl)

phosphonic acid

23

(4-((1-(3,4-bis(benzyloxy)phenyl)-16-ethyl-

5,8-dioxa-2,11,16-triazaoctadecan-18-yl)oxy)

phenyl)(6-hydroxy-2-(4-hydroxyphenyl)

benzo[b]thiophen-3-yl)methanone

24

(R)-5-((3-((21-(3,4-bis((4-fluorobenzyl)oxy)

phenoxy)-20-hydroxy-3,6,9,12,15-pentaoxa-

18-azahenicosyl)amino)-5-chlorophenyl)amino)

benzo[c][2,6]naphthyridine-8-carboxylic acid

25

(S)-3-(6-(3-((4-(1-(4-(benzyloxy)-3-

phenethoxyphenyl)-5,8,11,14-tetraoxa-2-

azahexadecan-16-yl)piperazin-1-yl)methyl)-

1,2,3,4-tetrahydroisoquinoline-2-carbonyl)

benzo[d][1,3]dioxol-5-yl)-N-(4-hydroxyphenyl)-N-

phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

26

(R)-1-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-

butylsulfonyl)quinazolin-7-yl)oxy)-24-

(3,4-bis((4-fluorobenzyl)oxy)phenoxy)-

6,9,12,15,18-pentaoxa-3,21-diazatetracosan-23-ol

27

N-(1-(3,4-bis(benzyloxy)phenyl)-5,8,11,14,17-

pentaoxa-2-azanonadecan-19-yl)-4-

phenylbutanamide

28

N-(1-(3,4-bis(benzyloxy)phenyl)-5,8,11,14,17,20,23-

heptaoxa-2-azapentacosan-25-yl)-4-

phenylbutanamide

29

(R)-N-(15-(3,4-bis((4-fluorobenzyl)oxy)phenoxy)-

14-hydroxy-3,6,9-trioxa-12-azapentadecyl)-

4-phenylbutanamide

30

(R)-N-(15-(3-((4-fluorobenzyl)oxy)phenoxy)-

14-hydroxy-3,6,9-trioxa-12-azapentadecyl)-4-

phenylbutanamide

31

N-(7-((1-(3,4-bis(benzyloxy)phenyl)-5,8,11-

trioxa-2-azatridecan-13-yl)(methyl)amino)-3H-

phenothiazin-3-ylidene)-N-methylmethanaminium

2,2,2-trifluoroacetate

32

(R)-N-(7-((15-(3,4-bis((4-fluorobenzyl)oxy)

phenoxy)-14-hydroxy-3,6,9-trioxa-12-

azapentadecyl)(methyl)amino)-3H-phenothiazin-

3-ylidene)-N-methylmethanaminium

2,2,2-trifluoroacetate

33

(R)-N-(7-((15-(3-((4-fluorobenzyl)oxy)phenoxy)-

14-hydroxy-3,6,9-trioxa-12-azapentadecyl)

(methyl)amino)-3H-phenothiazin-3-ylidene)-

N-methylmethanaminium 2,2,2-trifluoroacetate.

2. The cargo delivery system of claim 1 , wherein the target-binding ligand is a compound that specifically binds to a pathological protein, organelle, foreign invader or aggregate thereof.

3. The cargo delivery system of claim 2 , wherein the pathological protein is a causative protein that induces cancer, proteinophagy, rare or intractable disease, or genetic disease.

4. The cargo delivery system of claim 3 , wherein the proteinopathy is neurodegenerative disease, alpha-1 antitrypsin deficiency, keratopathy, retinitis pigmentosa, type 2 diabetes, or cystic fibrosis.

5. The cargo delivery system of claim 4 , wherein the neurodegenerative disease is at least one selected from the group consisting of Lyme borreliosis, fatal familial insomnia, Creutzfeldt-Jakob Disease (CJD), multiple sclerosis (MS), dementia, Alzheimer's disease, epilepsy, Parkinson's disease, stroke, Huntington's disease, Picks disease, amyotrophic lateral sclerosis (ALS), spinocerebellar ataxias, other Poly-Q diseases, hereditary cerebral amyloid angiopathy, familial amyloid polyneuropathy, primary systemic amyloidosis (AL amyloidosis), reactive systemic amyloidosis (AA amyloidosis), injection-localized amyloidosis, beta-2 microglobulin amyloidosis, hereditary non-neuropathic amyloidosis, Alexander disease and Finnish hereditary systemic amyloidosis.

6. A pharmaceutical composition comprising the cargo delivery system of claim 1 as an active ingredient.

7. A food composition comprising the cargo delivery system of claim 1 as an active ingredient.

8. A method for activating autophagy of a target in a subject, comprising administering to the subject a composition comprising the cargo delivery system of claim 1 in an effective amount.

Assignments (2)

Continuity (3)

References Cited (89)