IP Library › Granted Patent US 12,427,346
Granted Patent B2
US 12,427,346 · App. 17/262,082 · Granted Sep 30, 2025

P62 ligand compound, and composition for preventing, ameliorating or treating proteinopathies comprising the same

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)
Assignee: AUTOTAC INC.
C07C217/58A23L33/10A61K31/05A61K31/12A61K31/138A61K31/166A61K31/192A61K31/277A61K31/336A61K31/355A61K31/4015A61K31/4155A61K31/4184A61K31/421A61K31/428A61K31/4535A61K31/4709A61K31/4745A61K31/496A61K31/50A61K31/5025A61K31/506A61K31/517A61K31/5377A61K31/5415A61K31/551A61K31/565A61K39/3955A61K47/54A61K47/55A61K47/6803A61K47/6849A61P3/10A61P25/28C07C43/23C07C47/575C07C235/06C07C237/06C07C275/24C07C279/12C07D303/18C07B2200/07
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,427,346
App. No.
17/262,082
Granted
Sep 30, 2025
Kind
B2
Abstract

The present invention relates to a novel p62 ligand compound, a stereoisomer, hydrate, solvate or prodrug thereof, and a pharmaceutical or food composition for preventing or treating misfolded protein diseases comprising the same as an active ingredient. The p62 ligand compound according to the present invention can be usefully used as a pharmaceutical composition for the prevention, amelioration or treatment of various proteinopathies by activating selective autophagy in cells and thus selectively eliminating in vivo proteins, organelles and aggregates.

Claims (19)

1. A compound, a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or prodrug thereof, wherein the compound is selected from the group consisting of the following compounds:

1) 2-((2-((3,4-bis(benzyloxy)benzyl)amino)ethyl)amino)ethan-1-ol (YTK-1108);

2) 1-(2-((3-(benzyloxy)benzyl)amino)ethyl)guanidine (YTK-107);

3) 1-(2-((3-(phenethoxybenzyl)amino)ethyl)guanidine (YTK-207);

4) 2-(2-((3,4-bis(benzyloxy)benzyl)amino)ethoxy)ethan-1-ol (YTK-11-A76);

5) 1-(3,4-bis(benzyloxy)benzyl)-3-(2-hydroxyethyl)urea (ATB10041);

6) N-(3,4-bis(benzyloxy)benzyl)-2-hydroxyacetamide (ATB10042); and

7) (R)-2-amino-3-((3,4-bis(benzyloxy)benzyl)amino)propanoic acid (ATB10043).

2. A composition comprising the compound, a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or prodrug thereof according to claim 1 .

3. The composition according to claim 2 , wherein the composition is a pharmaceutical composition.

4. The composition according to claim 2 , wherein the composition is a food composition.

5. A method for increasing degradation of protein aggregates, comprising administering an effective amount of the compound, a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or prodrug thereof according to claim 1 to a subject in need thereof.

6. A method for activating autophagy, comprising administering an effective amount of the compound, a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or prodrug thereof according to claim 1 to a subject in need thereof.

7. A method for ameliorating or treating proteinopathies, comprising administering the compound, a pharmaceutically acceptable salt, stereoisomer, hydrate, solvate or prodrug thereof according to claim 1 to a subject in need thereof.

8. The method according to claim 7 , wherein the proteinopathy is neurodegenerative diseases, alpha-1 antitrypsin deficiency, keratopathy, retinitis pigmentosa, type 2 diabetes, or cystic fibrosis.

9. The method according to claim 8 , wherein the neurodegenerative diseases are 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), alpha-1 antitrypsin deficiency, Alexander syndrome, keratopathy, retinitis pigmentosa, type 2 diabetes, cystic fibrosis, injection-localized amyloidosis, beta-2 microglobulin amyloidosis, hereditary non-neuropathic amyloidosis, Alexander disease and Finnish hereditary systemic amyloidosis.

10. The method according to claim 6 , wherein the administering activates selective autophagy in the subject.

11. The composition according to claim 6 , wherein the autophagy is an autophagy activity of misfolded proteins and wherein the administering increases the autophagy activity of misfolded proteins in the subject.

12. The composition according to claim 6 , wherein the administering activates p62 proteins.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 22, 2024
From: PROTECH CO., LTD.
To: AUTOTAC INC.
Reel/Frame 066534/0137 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 12, 2021
From: KWON, YONG TAE; JI, CHANG HOON; KIM, HEE YEON; MUN, SU RAN; JUNG, CHAN HOON; JUNG, EUI JUNG; SUNG, KI WOON
To: PROTECH CO., LTD.
Reel/Frame 055574/0154 →
Continuity (2)
Provisional Application 62702473 · Jul 24, 2018
Related Publication 20210163399A1 · Jun 3, 2021
References Cited (112)
US 4167581A · Smith · 1979 [cited by applicant]
US 4471116A · Davidson et al. · 1984 [cited by applicant]
US 4857522A · Dipietro et al. · 1989 [cited by applicant]
US 9580382B2 · Xie · 2017 [cited by examiner]
US 20040009932A1 · Phelan et al. · 2004 [cited by applicant]
US 20150175607A1 · Xie · 2015 [cited by examiner]
US 20160031799A1 · Xie et al. · 2016 [cited by applicant]
US 20180243244A1 · Kwon et al. · 2018 [cited by applicant]
US 20180265452A1 · Xie · 2018 [cited by applicant]
US 20210024454A1 · Kwon et al. · 2021 [cited by applicant]
US 20210299253A1 · Kwon et al. · 2021 [cited by applicant]
US 20210347749A1 · Kwon et al. · 2021 [cited by applicant]
CN 102229602A · 2011 [cited by applicant]
CN 107848932 · 2018 [cited by applicant]
CN 112105598A · 2020 [cited by applicant]
EP 3338787A1 · 2018 [cited by applicant]
KR 1020150039894 · 2015 [cited by applicant]
KR 1020170021525 · 2017 [cited by applicant]
KR 1020170023045 · 2017 [cited by applicant]
KR 102149539B1 · 2020 [cited by applicant]
KR 102154294B1 · 2020 [cited by applicant]
WO WO2013022919 · 2013 [cited by applicant]
WO WO2013022919A1 · 2013 [cited by examiner]
WO 2015031710A1 · 2015 [cited by applicant]
WO WO2016200827 · 2016 [cited by applicant]
WO WO2017030292 · 2017 [cited by applicant]
WO WO2017079267 · 2017 [cited by applicant]
Chemical Abstracts Stn Registry Database, record for RN 774192-20-0. Entered STN Nov. 3, 2004 (Year: 2004). [cited by examiner]
Ji et al., “The AUTOTAC chemical biology platform for targeted protein degradation via the autophagy-lysosome system”, Nature Communications, (2022) 13:904 | https://doi.org/10.1038/s41467-022-28520-4 (14 pages). [cited by applicant]
Office Action issued Feb. 2, 2023 in U.S. Appl. No. 17/262,129. [cited by applicant]
Office Action issued Jul. 21, 2023 in Chinese Application No. 201980047607.6. [cited by applicant]
Office Action dated Oct. 19, 2023 in U.S. Appl. No. 17/262,129. [cited by applicant]
Barlow et al., “β-Adrenoceptor Stimulant Properties of Amidoalkylamino-Substituted 1-Aryl-2-ethanols and 1-(Aryloxy)-2-propanols”, J. Med. Chem., 1981, vol. 24, pp. 315-322. [cited by applicant]
International Search Report and Written Opinion of the International Searching Authority issued Nov. 11, 2019 in International Application No. PCT/KR2019/009203. [cited by applicant]
An et al., “Small-molecule PROTACs: An emerging and promising approach for the development of targeted therapy drugs”, EBioMedicine, 2018, vol. 36, pp. 553-562. [cited by applicant]
Xiong et al., “LINC01857 as an oncogene regulates CREB1 activation by interacting with CREBBP in breast cancer”, J. Cell. Physiol., 2019, pp. 1-9. [cited by applicant]
Puissant et al., “Resveratrol Promotes Autophagic Cell Death in Chronic Myelogenous Leukemia Cells via JNK-Mediated p62/SQSTM1 Expression and AMPK Activation”, Cancer Research, 2010, vol. 70, No. 3, pp. 1042-1052. [cited by applicant]
International Search Report and Written Opinion of the International Searching Authority issued Nov. 11, 2019 in International Application No. PCT/KR2019/009205. [cited by applicant]
Teramachi et al., “Blocking the ZZ domain of sequestosome1/p62 suppresses myeloma growth and osteoclast formation in vitro and induces dramatic bone formation in myeloma-bearing bones in vivo”, Leukemia, 2016, vol. 30, … [cited by applicant]
Office Action issued Feb. 1, 2022 in Japanese Application No. 2021-503886. [cited by applicant]
Lei et al., “Targeting oncoproteins for degradation by small molecules in myeloid leukemia”, Leukemia & Lymphoma, 2017, pp. 1-8 (9 pages total). [cited by applicant]
Yongtae Kwon, Autotac (Autophagy-targeting chimera) Technology, 2018, pp. 6-7 (7 pages total). [cited by applicant]
Bondeson et al., “Lessons in PROTAC design from selective degradation with a promiscuous warhead”, Cell Chem Biol., 2018, vol. 25, No. 1, pp. 78-87 (28 pages total). [cited by applicant]
PCT Search Report & Written Opinion for PCT/KR2019/009204, dated Nov. 11, 2019. [cited by applicant]
Ciechanover, A. & Kwon, Y.T., Exp Mol Med 47, e147 (2015). [cited by applicant]
Dikic, I. & Elazar, Z., Nat Rev Mol Cell Biol 19, 349-364 (2018). [cited by applicant]
Caccamo, A., Majumder, S., Richardson, A., Strong, R. & Oddo, S., J Biol Chem 285, 13107-20 (2010). [cited by applicant]
Ji, C.H. & Kwon, Y.T., Mol Cells 40, 441-449 (2017). [cited by applicant]
Jung, C. H., Ro, S. H., Cao, J., Otto, N. M. & Kim, D. H., FEBS Lett 584, 1287-95 (2010). [cited by applicant]
Ravikumar, B., Duden, R. & Rubinsztein, D.C., Hum Mol Genet 11, 1107-17 (2002). [cited by applicant]
Rodriguez-Navarro, J.A. et al., Neurobiol Dis 39, 423-38 (2010). [cited by applicant]
Sriram, S.M. & Kwon, Y.T., Nat Struct Mol Biol 17, 1164-5 (2010). [cited by applicant]
Sriram, S.M., Kim, B.Y. & Kwon, Y.T., Nat Rev Mol Cell Biol 12, 735-47 (2011). [cited by applicant]
Tasaki, T. et al., Mol Cell Biol 25, 7120-36 (2005). [cited by applicant]
Webb, J.L., Ravikumar, B., Atkins, J., Skepper, J.N. & Rubinsztein, D.C., J Biol Chem 278, 25009-13 (2003). [cited by applicant]
Communication dated Feb. 20, 2023, issued in Korean Application No. 10-2020-0092536. [cited by applicant]
Communication dated Feb. 20, 2023, issued in Korean Application No. 10-2020-0101379. [cited by applicant]
CAS Registry No. 1262521-61-8, 2011, 2 pages. [cited by applicant]
CAS Registry No. 562847-32-9, 2003, 1 page. [cited by applicant]
CAS Registry No. 99396-44-8, 1985, 2 pages. [cited by applicant]
CAS Registry No. 99342-74-2, 1985, 1 page. [cited by applicant]
CAS Registry No. 86955-68-2, 1984, 2 pages. [cited by applicant]
CAS Registry No. 77209-47-3, 1984, 1 page. [cited by applicant]
CAS Registry No. 76420-86-5, 1984, 2 pages. [cited by applicant]
CAS Registry No. 76420-85-4, 1984, 1 page. [cited by applicant]
CAS Registry No. 74867-70-2, 1984, 2 pages. [cited by applicant]
CAS Registry No. 58165-85-8, 1984, 1 page. [cited by applicant]
CAS Registry No. 2068956-48-7, 2017, 1 page. [cited by applicant]
CAS Registry No. 2000000-61-1, 2016, 1 page. [cited by applicant]
CAS Registry No. 1994480-74-8, 2016, 1 page. [cited by applicant]
CAS Registry No. 1881420-75-2, 2016, 1 page. [cited by applicant]
CAS Registry No. 1876857-32-7, 2016, 1 page. [cited by applicant]
CAS Registry No. 1874579-12-0, 2016, 2 pages. [cited by applicant]
CAS Registry No. 1869641-58-6, 2016, 1 page. [cited by applicant]
CAS Registry No. 1865340-43-7, 2016, 1 page. [cited by applicant]
CAS Registry No. 1859613-63-0, 2016, 1 page. [cited by applicant]
CAS Registry No. 1858409-61-6, 2016, 1 page. [cited by applicant]
CAS Registry No. 1827185-42-1, 2015, 1 page. [cited by applicant]
CAS Registry No. 1181454-24-9, 2009, 1 page. [cited by applicant]
CAS Registry No. 1181445-59-9, 2009, 1 page. [cited by applicant]
CAS Registry No. 940199-73-5, 2007, 1 page. [cited by applicant]
CAS Registry No. 892571-67-4, 2006, 1 page. [cited by applicant]
CAS Registry No. 861442-53-7, 2005, 1 page. [cited by applicant]
CAS Registry No. 861409-41-8, 2005, 1 page. [cited by applicant]
CAS Registry No. 774192-20-0, 2004, 1 page. [cited by applicant]
CAS Registry No. 190018-01-0, 1997, 1 page. [cited by applicant]
Australian Office Action dated Aug. 29, 2022 in Australian (AU) Application No. 2019312065. [cited by applicant]
John W.A. Findlay et al., “Relationships between Immunogen Structure and Antisera Specificity in the Narcotic Alkaloid Series”, Clinical Chemistry, 1981, vol. 27, No. 9, pp. 1524-1535 (12 pages total). [cited by applicant]
Maciej J. Stefanko et al., “Synthesis of functionalised polyethylene glycol derivatives of naproxen for biomedical applications”, Tetrahedron, 2008, vol. 64, No. 44, pp. 10132-10139 (8 pages total). [cited by applicant]
Nicolai Stuhr-Hansen et al., “Synthesis of Symmetrical and Non-Symmetrical Bivalent Neurotransmitter Ligands”, ChemistrySelect, 2016, vol. 1, No. 3, pp. 407-413 (7 pages total). [cited by applicant]
Office Action issued Dec. 18, 2023 by the United States Patent and Trademark Office in U.S. Appl. No. 17/262,157. [cited by applicant]
Bondeson et al., “Catalytic in vivo protein knockdown by small-molecule PROTACs”, Nature Chemical Biology, 2015, vol. 11, pp. 611-617 (9 pages total). [cited by applicant]
Lu et al., “Hijacking the E3 Ubiquitin Ligase Cereblon to Efficiently Target BRD4”, Chemistry and Biology, 2015, vol. 22, No. 6, pp. 755-763 (10 pages total). [cited by applicant]
Winter et al., “Phthalimide conjugation as a strategy for in vivo target protein degradation”, Science, 2015, vol. 348, No. 6241, pp. 1376-1381 (7 pages total). [cited by applicant]
Islam et al., “Autophagic Regulation of p62 is Critical for Cancer Therapy” Int. J. Mol. Sol. 2018, vol. 19, No. 1405, pp. 1-15 (15 pages total). [cited by applicant]
Keith D. Green et al., “Identification and Characterization of Inhibitors of the Aminoglycoside Resistance Acetyltransferase Eis from Mycobacterium tuberculosis”, ChemMedChem, 2012, vol. 7, pp. 73-77 (5 pages total). [cited by applicant]
“CAS RN774192-20-0”, Stn Registry Database, 2004, (14 pages total). [cited by applicant]
“CAS RN892571-80-1”, Stn Registry Database, 2006 (3 pages total). [cited by applicant]
“CAS RN892573-08-9”, Stn Registry Database, 2006 (4 pages total). [cited by applicant]
“CAS RN1181561-56-7”, Stn Registry Database, 2009 (3 pages total). [cited by applicant]
“CAS RN1181561-57-8”, Stn Registry Database, 2009 (4 pages total). [cited by applicant]
“CAS RN1217054-95-9”, Stn Registry Database, 2010 (3 pages total). [cited by applicant]
“CAS RN1869641-58-6”, Stn Registry Database, 2016 (4 pages total). [cited by applicant]
“CAS RN1874579-12-0”, Stn Registry Database, 2016 (3 pages total). [cited by applicant]
“CAS RN87265-43-8”, Stn Registry Database, 1984 (5 pages total). [cited by applicant]
REGISTRY(STN) [online], Nov. 16, 1984, CAS Registration No. 51169-99-4 (1 page total). [cited by applicant]
REGISTRY(STN) [online], Nov. 16, 1984, CAS Registration No. 47689-63-4 (1 page total). [cited by applicant]
REGISTRY(STN) [online], Jul. 27, 2004, CAS Registration No. 717091-45-7 (1 page total). [cited by applicant]
Kaiser, C. et al., “Adrenergic agents. 4. Substituted phenoxypropanolamine derivatives as potential β-adrenergic agonists,” Journal of Medicinal Chemistry, 1977, vol. 20, No. 5, pp. 687-692 (6 pages total). [cited by applicant]
Yadav, J. S. et al., “An efficient protocol for regioselective ring opening of epoxides using samarium triflate: Synthesis of propranolol, atenolol and RO363,” Journal of Molecular Catalysis A: Chemical, 2007, vol. 261,… [cited by applicant]
Nelson, W. L. et al., “The 3, 4-Catechol derivative of propranolol, a minor dihydroxylated metabolite,” Journal of Medicinal Chemistry, 1984, vol. 27, No. 7, pp. 857-861 (5 pages total). [cited by applicant]
Office Action issued Mar. 8, 2022 in Japanese Application No. 2021-503891. [cited by applicant]