US-20260124249-A1 - USE OF TNKS INHIBITORS FOR REGENERATION OF CARTILAGE

US20260124249A1US 20260124249 A1US20260124249 A1US 20260124249A1US-20260124249-A1

Abstract

The present disclosure relates to a method of treating arthritis by targeting Tankyrase. The methods according to the present disclosure can be advantageously used for regeneration of cartilage tissue and for treating osteoarthritis by maximizing the matrix synthesis in cartilage by inhibition of Tankyrase and regulation of other proteins related therewith.

Inventors

Jin-hong Kim
Sukyeong KIM
Sangbin HAN
Yongsik CHO

Assignees

LIFLEX SCIENCE INC.

Dates

Publication Date: 20260507
Application Date: 20260102

Claims (13)

1 . A method of promoting differentiation of an adult stem cell into a cartilage cell comprising: treating the adult stem cell with an effective amount of an inhibitor of Tankyrase for promoting differentiation of the adult stem cell into the cartilage cell, wherein the inhibitor of Tankyrase stabilizes Sox9 protein or increases the concentration of Sox9 protein, and promotes chondrogenic differentiation of the adult stem cell into a chondrocyte.
2 . The method of claim 1 , wherein the adult stem cell is a mesenchymal stem cell (MSC).
3 . The method of claim 1 , wherein the cartilage cell is an articular chondrocyte.
4 . The method of claim 1 , wherein the inhibitor of Tankyrase is an agent that binds to a nicotinamide sub-domain of ARTD catalytic domain of Tankyrase, an agent that binds to an adenosine sub-domain of Tankyrase, or an agent that binds to an unidentified domain of Tankyrase.
5 . The method of claim 4 , wherein the agent that binds to the nicotinamide sub-domain of ARTD catalytic domain of Tankyrase is XAV-939 {3,5,7,8-tetrahydro-2-[4-(trifluoromethyl)phenyl]-4H-thiopyrano[4,3-d]pyrimidine-4-one} or MN-64 {2-[4-(1-methylethyl)phenyl]-4H-1-benzopyran-4-one}.
6 . The method of claim 4 , wherein the agent that binds to the adenosine sub-domain of Tankyrase is selected from IWR-1 [4-(1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-methano-2H-isoindole-2-yl)-N-8-quinolynyl-benzamide], JW55 {N-[4-[[[[tetrahydro-4-(4-methoxyphenyl)-2H-pyran-4-yl]methyl]amino]carbonyl]phenyl]-2-purancarboxamide}, WIKI4 2-[3-[4-(4-methoxyphenyl)-5-(4-pyridynyl)-4H-1,2,4-triazol-3-yl]thio]propyl]-1 Hbenz[de]isoquinoline-1,3 (2H)-dion, TC-E5001 {3-(4-methoxyphenyl)-5-[[[4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]thio]methyl]-1,2,4-oxadiazol} and G007-LK {(E)-4-(5-(2-(4-(2-chlorophenyl)-5-(5-(methylsulfonyl)pyridine-2-yl)-4H-1,2,4-triazol-3-yl) vinyl)-1,3,4-oxadiazole-2-yl)benzonitrile}.
7 . The method of claim 4 , wherein the agent that binds to the unidentified domain of Tankyrase is selected from G244-LM {3,5,7,8-tetrahydro-2-[4-[2-(methylsulfonyl)phenyl]-1-piperazynyl]-4H-thiopyrano[4,3-d]pyrimidine-4-one} and AZ6102 {rel-2-[4-[6-[(3R,5S)-3,5-dimethyl-1-piperazynyl]-4-methyl-3-pyridynyl]phenyl]-3,7-dihydro-7-methyl-4H-pyrrolo[2,3-d]pyrimidine-4-one}.
8 . The method of claim 1 , wherein the inhibitor is a siRNA that suppresses the expression of Tankyrase gene into a Tankyrase protein.
9 . The method of claim 8 , wherein the siRNA comprises a sense strand consisting of SEQ ID NO: 25 and an antisense strand consisting of SEQ ID NO: 26, or a sense strand consisting of SEQ ID NO: 27 and an antisense strand consisting of SEQ ID NO: 28.
10 . The method of claim 1 , wherein the adult stem cell is an isolated adult stem cell.
11 . The method of claim 10 , wherein the isolated adult stem cell is an isolated mesenchymal stem cell.
12 . The method of claim 1 , wherein the method further comprises administering to a subject in need thereof the adult stem cell that has been treated with the inhibitor of Tankyrase.
13 . The method of claim 1 , wherein the adult stem cell treated with the inhibitor of Tankyrase is implanted into a cartilage lesion with a fibrin gel construct.

Description

CROSS-REFERENCE TO RELATED APPLICATION(S) This application is a continuation of application Ser. No. 15/930,940 filed May 13, 2020, which is fully incorporated by reference herein. INCORPORATION BY REFERENCE STATEMENT OF THE MATERIAL CONTAINED IN THE “SEQUENCE LISTING XML” FILE The Sequence Listing XML file submitted herewith is identified as follows: Date of Creation: Dec. 31, 2025; Sequence File Name: 171081.00058_SeqList.xml; Size in bytes: 163,882 bytes. BACKGROUND OF THE INVENTION Field of the Invention The present disclosure is related to the regeneration of cartilage. Description of the Related Art The conventional research related to osteoarthritis (OA) has been focused on the studies identifying the mechanism of degeneration of arthritis. Accordingly, the main factors leading to the degeneration mechanism are well known. Existing treatment strategies also focus on slowing the progression of the disease by suppressing degeneration factors, and these strategies cannot have the fundamental therapeutic effect on regenerating cartilage. Cartilage tissue is a tissue that gradually degrades when it begins to be damaged by aging or injury. Degenerative arthritis is a disease that is afflicted by 4.41 million people in Korea as of 2014, and the demand for treatment is rapidly increasing. However, drugs used to treat degenerative arthritis remain at pain relief levels such as hyaluronic acid and anti-inflammatory drugs. The treatments that induce fundamental regeneration of cartilage have not yet been developed, and research is in its infancy. Korean Patent Application Publication No. 2014-0144508 relates to a composition for treating damaged cartilage by regeneration thereof and discloses a composition comprising granulocyte macrophage-colony stimulating factor; GM-CSF as an effective ingredient for treating damaged cartilage by regenerating cartilage. Korean Patent Application Publication No. 2005-0012226 relates to regeneration of cartilage by use of TGF-beta and chondrocyte and discloses a method of treating osteoarthritis by treating the cells with members of TGF super family. However, no such documents disclose in connection with the treatment of cartilage regeneration targeting the factor disclosed herein. In order to fundamentally regenerate cartilage that has undergone degeneration, molecular mechanisms that regulate cartilage regeneration factors are needed to be identified, and the development of a treatment strategy through regulation of the factors is required. SUMMARY OF THE INVENTION The present disclosure is to provide a method treating arthritis or related disease through the regeneration of cartilage tissue by maximizing the ability of the chondrocytes to synthesize matrices by regulating Tankyrase-SOX9 pathway. In one aspect of the present disclosure, a method of treating arthritis in a subject in need thereof comprising the step of administering to the subject an effective amount of an inhibitor of Tankyrase; or a modified adult stem cell in which the expression of Tankyrase is suppressed or Tankyrase gene is knocked out, wherein the inhibitor of Tankyrase or the modified adult stem cell stabilizes the Sox9 protein or increases the concentration of the Sox9 protein by inhibiting the Tankyrase activity promoting the degradation of Sox9 protein. In one embodiment, the inhibitor of Tankyrase leads to chondrogenic differentiation of an adult stem cells leading to chondrogenic regeneration. In other embodiment, the inhibitor of Tankyrase is an agent that binds to a nicotinamide sub-domain or region of ARTD domain which is a catalytic domain of a Tankyrase protein, an agent that binds to an adenosine sub-domain of a Tankyrase protein or an agent that binds to an unidentified domain of a Tankyrase protein. In other embodiment, the agent that binds to a nicotinamide sub-domain of ARTD domain is XAV939 {3,5,7,8-tetrahydro-2-[4-(trifluoromethyl)phenyl]-4H-thiopyrano[4,3-d]pyrimidine-4-one} or MN-64 {2-[4-(1-methylethyl)phenyl]-4H-1-benzopyran-4-one}; the agent that binds to an adenosine sub-domain of a Tankyrase protein is IWR-1 [4-(1,3,3a,4,7,7a-hexahydro-1,3-dioxo-4,7-methano-2H-isoindole-2-yl)-N-8-quinolynyl-benzamide], JW55 {N-[4-[[tetrahydro-4-(4-methoxyphenyl)-2H-pyran-4-yl]methyl]amino]carbonyl]phenyl]-2-purancarboxamide}, WIKI4 2-[3-[4-(4-methoxyphenyl)-5-(4-pyridynyl)-4H-1,2,4-triazol-3-yl]thio]propyl]-1 Hbenz[de]isoquinoline-1,3 (2H)-dion, TC-E5001 {3-(4-methoxyphenyl)-5-[[[4-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazol-3-yl]thio]methyl]-1,2,4-oxadiazol or G007-LK {(E)-4-(5-(2-(4-(2-chlorophenyl)-5-(5-(methylsulfonyl)pyridine-2-yl)-4H-1,2,4-triazol-3-yl) vinyl)-1,3,4-oxadiazole-2-yl)benzonitrile}; and the agent that binds to anunidentified domain of a Tankyrase protein is G244-LM {3,5,7,8-tetrahydro-2-[4-[2-(methylsulfonyl)phenyl]-1-piperazynyl]-4H-thiopyrano[4,3-d]pyrimidine-4-one}, orAZ6102 {rel-2-[4-[6-[(3R,5S)-3,5-dimethyl-1-piperazynyl]-4-methyl-3-pyridynyl]phenyl]-3,7-dihydro-7-methy