RU-2026105377-A - Methods and compositions for treating cancer using a PRMT5 inhibitor

Inventors

• Лоу, Филип Стюарт
• СРИНИВАСАРАО, Маддури
• СЕНГУПТА, Сагник

Assignees

• ПУРДЬЮ РИСЕРЧ ФАУНДЕЙШН

Dates

Publication Date

20260507

Application Date

20240830

Priority Date

20230831

Claims (20)

1. 1. A conjugate of formula T-L-A, in which:
2. T is a ligand that targets prostate-specific membrane antigen (PSMA),
3. L is a linker, and
4. A contains a DNA repair enzyme inhibitor, wherein the DNA repair enzyme inhibitor is a protein arginine methyltransferase 5 (PRMT5) inhibitor, an ataxia telangiectasia mutated (ATM) protein inhibitor, or a DNA-protein kinase (DNA-PK) inhibitor.
5. 2. The conjugate of claim 1, wherein T is:
6. 3. The conjugate of claim 1, wherein T is:
7. wherein R 1 and R 2 are independently selected from hydrogen, a carboxylic acid that is optionally substituted, malonic acid, succinic acid, glutamic acid and adipic acid.
8. 4. The conjugate of claim 3, wherein the substituted carboxylic acid is thioacetic acid or thiopropionic acid.
9. 5. The conjugate of claim 1, wherein T is a urea formed from (a) an aminodicarboxylic acid or a derivative thereof and (b) an aminodicarboxylic acid or a derivative thereof, wherein (a) and (b) may be the same or different.
10. 6. The conjugate of any one of claims 1 to 5, wherein L comprises a chain of atoms of length from about 3 atoms to about 30 atoms.
11. 7. The conjugate of any one of claims 1 to 6, wherein L comprises a chain of atoms of length from about 5 Å to about 45 Å.
12. 8. The conjugate of any one of claims 1 to 7, wherein L comprises a peptide.
13. 9. The conjugate of any one of claims 1 to 8, wherein L comprises one or more phenylalanine residues, each of which is independently optionally substituted.
14. 10. The conjugate of any one of claims 1 to 9, wherein L comprises at least one phenylalanyl-phenylalanyl, wherein at least one phenyl is independently optionally substituted.
15. 11. The conjugate of any one of claims 1-10, wherein L comprises (polyethylene glycol) n (POEGn), (polyethylene glycol) n (PEGn) or a mixture thereof, wherein n = 1-36.
16. 12. The conjugate of any one of claims 1-11, wherein L comprises a disulfide.
17. 13. The conjugate of claim 1, wherein the PRMT5 inhibitor comprises the JNJ-64619178 radical or the GSK3326595 radical.
18. 14. The conjugate of claim 1, wherein the ATM inhibitor comprises the AZD0156 radical.
19. 15. The conjugate of claim 1, wherein the DNA-PK inhibitor comprises the radical nedisertib, AZD7648, KU57748, torin 2, PI-103, NU7026, samatolisib, PIK 90, CC-115, PIK-75 hydrochloride, VX-984, KU-0060648, BAY-8400, DNA-PK-LN-2, DNA-PK-TN-1, DNA-PK-TN-4, DNA-PK-TN-5, DNA-PK-TN-6, XRD-0394, NU5455, STL127705, PI-103 hydrochloride, LTURM34, ZL-2201 free base, DNA-PK-IN-14, DNA-PK-IN-10, DNA-PK-IN-11 or DNA-PK-IN-13.
20. 16. The conjugate of any one of claims 1-15, further comprising an albumin-binding group.