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KR-20260065746-A - Compounds specific to Granzyme B and their uses

KR20260065746AKR 20260065746 AKR20260065746 AKR 20260065746AKR-20260065746-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 said compound and pharmaceutical composition in cancer treatment and/or imaging.

Inventors

  • 빌처, 제프리 말콤
  • 시옹, 후이
  • 호클러, 캐리
  • 카스타나레스, 마크 에이.
  • 리버만, 브라이언
  • 장, 준티엔
  • 발렌수엘라, 프란시스코 에이.

Assignees

  • 사이토사이트 바이오파마 인코포레이티드

Dates

Publication Date
20260511
Application Date
20240607
Priority Date
20230607

Claims (20)

  1. Compound of formula (I) or its stereoisomers, tautomers, or salts: Here: M is a radioactive moiety; A is a chelating moiety that chelates a radioactive moiety; 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)-; Y is CH or N; 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 having 1 to 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.
  2. In claim 1, the compound having the chemical formula (Ia):
  3. A compound according to claim 1 or 2, wherein X is -CH 2 C(O)-.
  4. In paragraph 3, the compound having the chemical formula (Ib):
  5. A compound according to any one of claims 1 to 4, wherein L has 1 to 5 amino acid residues; optionally, L has one or more non-naturally occurring amino acid residues.
  6. In any one of claims 1 to 5, L is a compound having an amino acid sequence selected from the group consisting of the following: Glu-Gly-Gly, Glu-βAla-βAla, γGlu, D γGlu, γGlu-βAla, D Glu-βAla-βAla, D Glu-AEA, D Glu-AEEA-AEEA, D Glu- D Glu-AEA, D Glu- D Glu-βAla-βAla, βAla- D Glu-βAla, Discrete-βAla-βAla, N-acid-βAla-βAla, and βAla-N-acid-βAla.
  7. A compound according to any one of claims 1 to 6, wherein 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-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), a limited complexing agent (RESCA), or a MACROPA.
  8. A compound according to any one of claims 1 to 7, wherein the radioactive moiety of M is a therapeutic radioisotope.
  9. In paragraph 8, the therapeutic radioisotope is 67 Cu, 90 Y, 177 Lu, 225 Ac, 47 Sc, 131 I, 153 Sm, 161 Tb, 211 At, 212 Pb, 212 Bi, 223 Ra, or 227 Th; and optionally a compound in which the therapeutic radioisotope is 90 Y.
  10. A compound according to any one of claims 1 to 9, wherein the chelating moiety is NOTA or DOTA and the therapeutic radioisotope is 90 Y, 177 Lu, or 225 Ac.
  11. A compound according to any one of claims 1 to 10, wherein the chelating moiety is NODA and the therapeutic radioisotope is 47 Sc or 67 Cu.
  12. In paragraph 1, the compound has one of the following structures: Here, M is 177 Lu, 90 Y, 225 Ac, or 213 Bi, or Here, M is 177 Lu, 90 Y, 225 Ac, or 213 Bi.
  13. A pharmaceutical composition comprising a compound of any one of claims 1 to 12 and a pharmaceutically acceptable carrier.
  14. As a method for treating cancer in a subject, the above method (a) a method comprising the step of administering an effective amount of a compound of any one of claims 1 to 12 or a pharmaceutical composition containing the same to a subject in need thereof.
  15. A method according to claim 14, further comprising the step of administering an immunotherapeutic agent to a subject prior to step (a).
  16. A method according to claim 14 or 15, wherein the immunotherapeutic agent is an immune checkpoint inhibitor that is optionally a PD1 inhibitor, or a genetically engineered T cell expressing a chimeric antigen receptor (CAR).
  17. A method according to any one of claims 14 to 16, further comprising the step of administering an imaging agent to a subject to image Granzyme B prior to step (a).
  18. A method in which, in any one of paragraphs 14 through 17, the subject is further treated with one or more additional therapeutic agents.
  19. In paragraph 18, a method in which one or more additional therapeutic agents are selected from the group consisting of anti-inflammatory agents, steroids, immunotherapeutic agents, and chemotherapy agents.
  20. A cancer treatment kit comprising a first container having a compound of any one of claims 1 to 12 or a pharmaceutical composition containing the same.

Description

Compounds specific to Granzyme B and their uses Cross-reference regarding related applications This application claims the benefit of U.S. Provisional Application No. 63/506,718 filed June 7, 2023, the contents of which are incorporated herein by reference in their entirety. Technology field The present disclosure relates to a radioactive compound useful as a therapeutic agent, and more specifically, to a radioactive compound useful for identifying Granzyme B and eliminating cancer cells containing it. Background Technology 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 subsequently enters cancer cells, primarily through perforin vacancies, and activates multiple substrates leading to the activation of the caspase cascade. As a downstream effector of oncological cytotoxic T cells, Granzyme B has been used as an early biomarker for tumors responding to immunotherapy. There is a need to develop effective granzyme B imaging agents and new compounds that act as therapeutic agents for treating immunomodulatory abnormalities such as cancer. Description of the invention 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 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; 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)-; Y is CH or N; 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 having 1 to 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. In some embodiments, the compound has the 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 has the chemical formula (Ib): In any of the compounds of formula (I), for example, in the compounds of formula (Ia) or formula (Ib) provided herein, L may be a peptide having 1 to 5 amino acid residues (1, 2, 3, 4, or up to 5). In some cases, L may have one or more non-naturally occurring amino acid residues. Exemplary peptides of L are provided below: Glu-Gly-Gly, Glu-βAla-βAla, γGlu, D γGlu, γGlu-βAla, D Glu-βAla-βAla, D Glu-AEA, D Glu-AEEA-AEEA, D Glu- D Glu-AEA, D Glu- D Glu -βAla-βAla, βAla- D Glu-βAla, diacid-βAla-βAla, N - acid-βAla-βAla, or βAla-N-acid-βAla. In any of the compounds of formula (I), for example, in the compounds of formula (Ia) or formula (Ib) 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-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), a limited complexing agent (RESCA), or MACROPA. In any of the compounds of formula (I), for example, in the compounds of formula (Ia) or formula (Ib) provided herein, the radioactive moiety of M may be a therapeutic radioisotope. Examples include, but are not limited to, 67 Cu, 90 Y, 177 Lu, 225 Ac, 47 Sc, 131 I, 153 Sm, 161 Tb, 211 At, 212 Pb, 212 Bi, 223 Ra, or 227 Th. In some specific examples, the therapeutic radioisotope is 90 Y. In some embodiments, in the compounds provided herein, the chelating moiety is NOTA or DOTA and the therapeutic radioisotope is 90 Y, 177 Lu, or 225 Ac. In other examples, the chelating moiety is NODA and the therapeutic radioisotope is 47 Sc or 67 Cu. In some examples, the compounds disclosed herein have the following structures: Here, M is 177 Lu, 90 Y, 225 Ac, or 213 Bi. In another example, the compound disclosed herein has the following structure: Here, M is 177 Lu, 90 Y, 225 Ac, or 213 Bi. A pharmaceutical composition comprising one or more of the compounds of the aforementioned chemical formula (I) is also provided and is within the scope of the present disclosure. In another aspect, the present disclosure features a method for treating cancer in a subject, said method comprising administering an effective amount of any of the compounds of formula (I) disclosed herein or a pharmaceutical composition comprising the same as disclosed herein to a subject in need thereof. In some cases, the subject may be administered an immunotherapeutic agent before receiving the compound of formula (I). Exemplary immunotherapeutic agents include