AUTOTAC chimeric compound, and composition for preventing, ameliorating or treating diseases through targeted protein degradation comprising the same
The present invention relates to a novel AUTOTAC chimeric compound in which a new p62 ligand and a target-binding ligand are connected by a linker, a stereoisomer, hydrate, solvate or prodrug thereof, and a pharmaceutical or food composition for the prevention or treatment of diseases by degrading the target protein including the same as an active ingredient. They can target specific proteins to adjust their concentrations, and can also deliver drugs and other small molecule compounds to lysosomes. The AUTOTAC chimeric compound according to the present invention can be usefully used as a pharmaceutical composition for the prevention, amelioration or treatment of various diseases by selectively eliminating specific proteins.
1. A compound selected from the group consisting of the following compounds 1 to 13:
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; and
13) (R)-1-(3-phenethoxyphenoxy)-3-((2-(2-(2-((6-(trifluoromethoxy))benzo[d]thiazol-2-yl)amino)ethoxy)ethoxy)ethyl)amino)propan-2-ol,
or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.
2. A composition comprising the compound according to claim 1 , a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof.
3. The composition according to claim 2 , wherein the composition is a pharmaceutical composition.
4. A method for activating selective autophagy, comprising administering an effective amount of the compound of claim 1 , a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof to a subject in need thereof.
5. The method according to claim 4 , wherein activating selective autophagy is increasing autophagic delivery or degradation of targets comprising pathological misfolded proteins, aggregates, organelles and/or pathogens thereof.
6. The method according to claim 4 , wherein the activating selective autophagy is increasing degradation of viruses and bacteria that have invaded cells.
7. The method according to claim 4 , wherein activating selective autophagy is delivering drugs or small molecule compounds in tandem with target proteins, organelles or pathogens to autophagic membranes.
8. The method according to claim 4 , wherein the activation of selective autophagy is mediated by the autophagy target receptor p62/SQSTM1, comprising self-oligomerization, conformational activation and delivery to autophagic membranes.
9. The method according to claim 4 , wherein activating selective autophagy is increased delivery of target proteins, organelles and/or pathogens to lysosomes by connecting these targets to p62.
10. The method according to claim 4 , wherein the method comprises prevention, amelioration or treatment of cancer, or proteinopathy.
11. The method according to claim 10 , wherein the proteinopathy is neurodegenerative diseases, alpha-1 antitrypsin deficiency, keratopathy, retinitis pigmentosa, type 2 diabetes, or cystic fibrosis.
12. The method according to claim 11 , wherein the neurodegenerative diseases are 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.