Search

KR-20260068055-A - Prodrugs for Compounds Specific to Granzyme B and Their Uses

KR20260068055AKR 20260068055 AKR20260068055 AKR 20260068055AKR-20260068055-A

Abstract

A compound capable of binding to granzyme B and comprising a radioactive moiety, e.g., a compound of formula (I), and a pharmaceutical composition comprising the same. The present specification also provides the use of the compound and the pharmaceutical composition in cancer treatment, and a kit and method for cancer treatment.

Inventors

  • 빌서, 제프리, 말콤
  • 시옹, 후이
  • 호어클러, 캐리
  • 카스타나레스, 마크, 에이.
  • 리버먼, 브라이언
  • 장, 웨이
  • 황, 쉬안
  • 장, 준티안

Assignees

  • 사이토사이트 바이오파마 인코포레이티드

Dates

Publication Date
20260513
Application Date
20240607
Priority Date
20230607

Claims (20)

  1. Compound of the following chemical formula (I) or its stereoisomers, tautomers, or salts: Here, M is a radioactive moiety; A is a chelating moiety that chelates a radioactive moiety; B is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclyl; optionally, B is a 6-membered ring; X is selected from the group consisting of -CH 2 C(NH)-, -CH 2 C(O)-, -CH 2 C(S)-, -NHC(NH)-, -NHC(O)-, -NHC(S)-, -OC(NH)-, -OC(O)-, and -OC(S)-, and optionally X is -CH 2 C(O)- or -NHC(S)-; Z is selected from the group consisting of -CH 2 -, -CH 2 C(NH)-, -CH 2 C(O)-, -CH 2 C(S)-, -NHC(NH)-, -NHC(O)-, -NHC(S)-, -OC(NH)-, -OC(O)-, and -OC(S)-; L is a peptide linker containing 1-6 amino acid residues; R1 is H or C1-6 alkyl, and optionally R1 is H or methyl; R2 is a C1-6 alkyl or C3-6 cycloalkyl; R3 is a C1-6 alkyl.
  2. A compound according to claim 1, wherein R₂ is a C1-6 alkyl.
  3. A compound according to claim 1 or 2, wherein R2 is a C4 alkyl.
  4. In paragraph 3, a compound in which R 2 is sec-butyl (-CH(CH 3 )CH 2 CH 3 ).
  5. In paragraph 4, the compound having the structure of the following chemical formula (Ia), or a stereoisomer, tautomer, or salt thereof: .
  6. A compound according to any one of claims 1 to 5, wherein X is CH 2 C(O)- or -NHC(S)-.
  7. In paragraph 6, the compound or its stereoisomer, tautomer, or salt having the structure of the following chemical formula (Ib): .
  8. A compound according to any one of claims 1 to 7, wherein R3 is a C1 alkyl.
  9. In paragraph 8, a compound in which R3 is methyl ( -CH3 ).
  10. In claim 9, the compound having the structure of the following chemical formula (Ic), or a stereoisomer, tautomer, or salt thereof: .
  11. A compound according to any one of claims 1 to 10, wherein B is a 6-membered ring.
  12. A compound according to any one of claims 1 to 11, wherein Z is -CH₂- or -CH₂C (O)-.
  13. In paragraph 12, a compound or its stereoisomer, tautomer, or salt having one of the structures of the following chemical formulas (Ic-A), (Ic-B), and (Ic-C): .
  14. A compound or a stereoisomer, tautomer, or salt thereof, wherein the compound has one of the structures of the following chemical formulas (Ic-Aa), (Ic-Ab), (Ic-Ba), (Ic-Bb), (Ic-Ca), and (Ic-Cb): .
  15. In any one of claims 1 to 11, the compound or its stereoisomer, tautomer, or salt, wherein the compound has the structure of the following chemical formula (Id): .
  16. A compound according to any one of claims 1 to 15, wherein the chelating moiety A is 1,4,7-triazcyclononan-N,N',N"-triacetic acid (NOTA), 1,4,7-triazcyclononan-4,7-diyldiaacetic acid (NODA), 1,4,7,10-tetraazcyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazcyclododecane-1,4,7-triacetic acid (DO3A), a limited complexing agent (RESCA), or a MACROPA.
  17. A compound in any one of paragraphs 1 through 16, wherein A is NODA.
  18. A compound according to any one of claims 1 to 17, wherein L comprises 1 to 3 amino acid residues.
  19. A compound according to any one of claims 1 to 17, wherein L comprises 3 to 6 amino acid residues.
  20. In any one of paragraphs 1 through 19, L Gly, Gly-Gly, Gln-Gly, Glu, Glu-Gly, Glu-Gly-Gly, Glu-βAla-βAla, D Glu, D Glu-βAla-βAla, D Glu-Gly-Gly, D Glu-AEA, D Glu-AEEA-AEEA, D Glu- D Glu-AEA, D Glu- D Glu-βAla-βAla, γGlu, γGlu-βAla, D γGlu, Lys-Gly, Arg-Gly, N - acid-βAla-βAla, βAla- N -acid-βAla, βAla-Glu-Gly-Gly, βAla- D Glu-βAla, and Discrete-βAla-βAla A compound having an amino acid sequence selected from the group consisting of

Description

Prodrugs for Compounds Specific to Granzyme B and Their Uses Cross-reference of related applications This application claims the benefit of U.S. provisional application No. 63/506,732 filed June 7, 2023, the contents of which are incorporated herein by reference in their entirety. Technology field The present disclosure relates to a prodrug radioactive compound that can be converted into an active form useful as a therapeutic agent in vivo, and more specifically, to a prodrug radioactive compound that is converted into an active compound specific to Granzyme B and can eliminate cancer cells containing it. Granzyme B is the most commonly found serine protease in the granules of natural killer cells and cytotoxic T cells. Granzyme B is released along with the vacancy-forming protein perforin at the immunological synapse formed between T cells and their targets. A portion of the released Granzyme B enters cancer cells primarily through perforin vacancies, activating multiple substrates that lead to the activation of the caspase cascade. As a downstream effector of tumor cytotoxic T cells, Granzyme B has been used as an early biomarker for tumors responding to immunotherapy. There is a need to develop new compounds that act as effective granzyme B imaging agents, and therapies to treat immunomodulatory abnormalities such as cancer. The present disclosure is based at least partially on the development of a prodrug compound that can be converted, for example, into an active granzyme B (GZB)-binding compound in vivo. Such a prodrug compound (i.e., a precursor form of a GZB-binding compound) exhibits superior features such as the production of a single isomer, synthesis with reliable stereochemical results, and the easy release of the active GZB-binding compound in vivo, or a combination thereof. Such a precursor form of a granzyme B (GZB)-binding compound can be used, for example, to target GZB for therapeutic purposes. The present application provides a radioactive compound capable of targeting granzyme B and its use as a therapeutic agent for treating diseases associated with granzyme B, such as cancer. In some aspects, the present invention provides a compound having the structure of the following formula (I) or a stereoisomer, tautomer, or salt thereof. In chemical formula (I), M represents a radioactive moiety; A is a chelating moiety that chelates the radioactive moiety of M; B is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclyl; optionally, B is a 6-membered ring; X is -CH 2 C(NH)-, -CH 2 C(O)-, -CH 2 C(S)-, -NHC(NH)-, -NHC(O)-, -NHC(S)-, -OC(NH)-, -OC(O)-, and -OC(S)-, and optionally X is -CH 2 C(O)- or -NHC(S)-; Z is -CH₂- , -CH₂C (NH)-, -CH₂C (O)-, -CH₂C(S)-, -NHC (NH)-, -NHC(O)-, -NHC(S)-, -OC(NH)-, -OC(O)-, or -OC(S)-; optionally, Z is -CH₂- or -CH₂C (O)-; L is a peptide linker containing 1-6 amino acid residues; R1 is H or C1-6 alkyl, and optionally R1 is H or methyl; R2 is a C1-6 alkyl or C3-6 cycloalkyl; R3 is a C1-6 alkyl. In some embodiments, R2 is a C1-6 alkyl. In some examples, R2 is a C4 alkyl. In specific examples, R2 is sec-butyl(-CH( CH3 ) CH2CH3 ) . In some embodiments, the compound is a compound of the following chemical formula (Ia): In any of the compounds of formula (I), for example, in the compound of formula (Ia), X can be -CH₂C (O)-. In some cases, the compound is a compound of the following chemical formula (Ib): In any of the compounds of formula (I), for example, in the compounds of formula (Ia) or formula (Ib) provided herein, R₃ is a C₆alkyl . For example, R₃ is methyl ( -CH₃ ). In any of the compounds of formula (I), for example, in the compounds of formula (Ia) or formula (Ib) provided herein, R₃ is a C₂alkyl . For example, R₃ is ethyl ( -CH₂CH₃ ). In some cases, the compound is a compound of the following formula (Ic): In any of the compounds of formula (I), for example, in the compounds of formula (Ia), formula (Ib), or formula (Ic) provided herein, B may be a 6-membered ring. Alternatively or additionally, in any of the compounds of formula (I), for example, in the compounds of formula (Ia), formula (Ib), or formula (Ic) provided herein, Z may be -CH₂- or -CH₂C (O)-. In some cases, the compound has one of the structures of the following chemical formulas (Ic-A), (Ic-B), or (Ic-C): In some cases, the compound has one of the structures of the following chemical formulas (Ic-Aa), (Ic-Ab), (Ic-Ba), (Ic-Bb), (Ic-Ca), and (Ic-Cb): In some cases, the compound has the following chemical formula (Id): In any of the compounds of formula (I), for example, in the compounds of formulas (Ia), (Ib), (Ic), or (Id) provided herein, the chelating moiety A may be 1,4,7-triazcyclononan-N,N',N"-triacetic acid (NOTA), 1,4,7-triazcyclononan-4,7-diyldiaacetic acid (NODA), 1,4,7,10-tetraazcyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazcyclododecane-1,4,7-triacetic acid (DO3A), a limited complexing agent (RESCA), or a MACROPA. In any of the compou