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US-12616761-B2 - CXCR4-targeting compounds

US12616761B2US 12616761 B2US12616761 B2US 12616761B2US-12616761-B2

Abstract

The present disclosure relates to peptidic compounds of Formula A, A-II, A-III, B, or C, or salt or solvate thereof, compositions thereof, and methods of use thereof. The compounds of the present disclosure are useful for targeting CXCR4 for purposes such as imaging and/or therapeutics.

Inventors

  • François BÉNARD
  • Kuo-shyan Lin
  • Zhengxing Zhang
  • Daniel KWON
  • David Perrin
  • Mijhajlo TODOROVIC
  • Jerome LOZADA
  • Lee Lee LI

Assignees

  • PROVINCIAL HEALTH SERVICES AUTHORITY
  • THE UNIVERSITY OF BRITISH COLUMBIA

Dates

Publication Date
20260505
Application Date
20240627

Claims (20)

  1. 1 . A compound of Formula A-II or salt or solvate thereof: wherein: —NH—CH(R 2a )—C(O)— in Formula A-II forms a Tyr residue, a Phe residue, a (4-NO 2 )-Phe residue, a (4-NH 2 )-Phe residue, a hTyr residue, a (3-I)Tyr residue, a Glu residue, a Gln residue, or a D-Tyr residue; —NH—CH(R 3a )—C(O)— in Formula A-II forms a Lys(iPr) residue, an asymmetric Arg(Me) 2 residue, or a Arg(Me) residue; —NH—CH(R 4a )—C(O)— in Formula A-II forms a D-Arg residue or a D-hArg residue; —NH—CH(R sa )—C(O)— in Formula A-II forms a 2-(Ant)Ala residue, a 2-Nal residue, a Trp residue, a (4-NH 2 )Phe residue, a hTyr residue, or a Tyr residue; —NH—CH(R 6a )—C(O)— in Formula A-II forms a His residue, a D-His residue, a D-Glu residue, a D-Gln residue, a D-Ala residue, a D-Phe residue, a D-Ser residue, a D-Dab residue, a D-Dap residue; R 8a is R 8b R 8c , wherein R 8b is a linear C 1 -C 5 alkylenyl, C 2 -C 5 alkenylenyl, or C 2 -C 5 alkynylenyl, wherein R 8c is —N(R 8d ) 2-3 or guanidino, wherein each R 8d is independently —H or a linear or branched C 1 -C 3 alkyl; R 9a is —C(O)NH 2 , —C(O)—OH, or —R 9b -[linker]-R X n1 ; R 9b is —C(O)NH—; R A7a is C 1 -C 3 alkylenyl; R A10 is absent or -[linker]-R X n1 ; when R A10 is absent, then R A1a is a linear C 1 -C 5 alkyl optionally substituted with a single substituent selected from: —SH, —OH, amino, carboxy, guanidino, —NH—C(O)—CH 3 , —S—C(O)—CH 3 , —O—C(O)—CH 3 , —NH—C(O)-(phenyl), —S—C(O)-(phenyl), —O—C(O)-(phenyl), —NH—(CH 3 ) 1-2 , —NH 2 —CH 3 , —N(CH 3 ) 2-3 , —S—CH 3 , —O—CH 3 , or a branched C 1 -C 10 alkyl, alkenyl, or alkynyl; when R A10 is -[linker]-R X n1 , then R A1a is R A1e R A1f , wherein R A1e is a linear C 1 -C 5 alkylenyl, C 2 -C 5 alkenylenyl, or C 2 -C 5 alkynylenyl, and R A1f is —NH—C(O)—, —C(O)—, —O—, —C(O)NH—, —C(O)—N(CH 3 )—, —NHC(S)—, —C(S)NH—, —N(CH 3 )C(S)—, —C(O)N(CH 3 )—, —N(CH 3 )C(O)—, —C(S)N(CH 3 )—, —NHC(S)NH—, —NHC(O)NH—, —S—, —S(O)—, —S(O)—O—, —S(O) 2 —, —S(O) 2 —NH—, —S(O)—NH—, —NHNHC(O)—, —C(O)NHNH—, or polyethylene glycol; the linker is each independently a linear or branched chain of 1-10 units of X 1 L 1 and/or X 1 (L 1 ) 2 , wherein: each X 1 is, independently, a linear, branched, and/or cyclic C 1 -C 15 alkylenyl, C 2 -C 15 alkenylenyl or C 2 -C 15 alkynylenyl wherein 0-6 carbons are independently replaced by N, S, and/or O heteroatoms, and substituted with 0-3 groups independently selected from one or a combination of oxo, hydroxyl, sulfhydryl, halogen, guanidino, carboxylic acid, sulfonic acid, sulfinic acid, and/or phosphoric acid; each L 1 is independently —NH—C(O)—, —NH—, —C(O)—, —O—, —C(O)NH—, —C(O)—N(CH 3 )—, —NHC(S)—, —C(S)NH—, —N(CH 3 )C(S)—, —C(O)N(CH 3 )—, —N(CH 3 )C(O)—, —C(S)N(CH 3 )—, —NHC(S)NH—, —NHC(O)NH—, —S—, —S(O)—, —S(O)—O—, —S(O) 2 —, —S(O) 2 —O—, —S(O) 2 —NH—, —S(O)—NH—, —Se—, —Se(O)—, —Se(O) 2 —, —NHNHC(O)—, —C(O)NHNH—, —OP(O)(O − )O—, -phosphamide-, -thiophosphodiester-, —S-tetrafluorophenyl-S—, or polyethylene glycol; or alternatively, the linker together with R A1f forms a linear or branched peptide linker (Xaa) 1-5 , wherein each Xaa is independently selected from a proteinogenic amino acid residue or a nonproteinogenic amino acid residue; and wherein the amino group in each Xaa is optionally methylated; each n1 is independently 0, 1 or 2; each R X is a therapeutic moiety, a fluorescent label, a radiolabeled group, a group capable of being radiolabelled, or a group capable of being radiolabelled that is in complex with a radioisotope or a radioisotope-bound metal; wherein 0-3 peptide backbone amides are independently replaced with or thioamide; wherein 0-3 peptide backbone amides are N-methylated; and optionally, the compound is C-terminally amidated.
  2. 2 . The compound of claim 1 , wherein R A10 is -[linker]-R X n1 .
  3. 3 . The compound of claim 1 , wherein the linker is X 1 L 1 , X 1 L 1 X 1 L 1 , or X 1 L 1 X 1 L 1 X 1 L 1 , wherein each X 1 is same or different and each L 1 is same or different; and X 1 is wherein each R 11 is independently a carboxylic acid, a sulfonic acid, a sulfinic acid, or a phosphoric acid.
  4. 4 . The compound of claim 3 , wherein each X 1 is wherein each R 11 is independently a carboxylic acid, a sulfonic acid, a sulfinic acid, or a phosphoric acid.
  5. 5 . The compound of claim 1 , wherein the linker together with R A1f forms a linear or branched peptide linker (Xaa) 1-5 , wherein: a) at least one Xaa is selected from cysteic acid, Glu, Asp, or 2-aminoadipic acid (2-Aad); and wherein the group in each Xaa is optionally methylated; or b) at least one Xaa is selected from Dap, Dab, Orn, Arg, hArg, Agb, Agp, Acp, Pip, or NE, N ϵ , N ϵ -trimethyl-lysine; and wherein the group in each Xaa is optionally methylated.
  6. 6 . The compound of claim 1 , wherein the linker together with R A1f forms a single amino acid residue selected from: a) cysteic acid, Glu, Asp, or 2-aminoadipic acid (2-Aad); and wherein the group in Xaa is optionally methylated; or b) D-Arg, L-Arg, D-hArg, L-hArg, or Pip; and wherein the group in Xaa is optionally methylated.
  7. 7 . The compound of claim 1 , wherein zero peptide backbone amides are replaced.
  8. 8 . The compound of claim 1 , wherein zero peptide backbone amides are N-methylated.
  9. 9 . The compound of claim 1 , wherein the compound of Formula A-II, or a salt or solvate thereof have the following combinations: —NH—CH(R 2a )—C(O)— forms a Tyr residue; —NH—CH(R 3a )—C(O)— forms a Lys(iPr) residue; —NH—CH(R 4a )—C(O)— forms a D-Arg residue; —NH—CH(R A7a )—C(O)— forms a D-amino acid residue, wherein R A7a is C 1 -C 3 alkyenyl; and —NH—CH(R 8a )— together with —C(O)— from R 9a forms a Lys(iPr) residue.
  10. 10 . The compound of claim 9 , wherein —NH—CH(R 6a )—C(O)— forms a D-Ala residue or a D-Gln residue; and —NH—CH(R 5a )—C(O)— forms a 2-Nal residue or a (4-NH 2 )Phe residue.
  11. 11 . The compound of claim 9 , wherein R A10 is -[linker]-R X n1 , R A1e is linear C 1 -C 5 alkylenyl, and R A1f is —NH—C(O)—.
  12. 12 . The compound of claim 1 , wherein at least one R X is a radiolabeled group or a group capable of being radiolabelled, wherein each group capable of being radiolabelled is independently selected from: a metal chelator optionally in complex with a radiometal or radioisotope-bound metal; a prosthetic group containing trifluoroborate (BF 3 ); or a prosthetic group containing a silicon-fluorine-acceptor moiety, a sulphonyl fluoride, or a phosphoryl fluoride.
  13. 13 . The compound of claim 12 , wherein the metal chelator is in complex with the radioisotope.
  14. 14 . The compound of claim 12 , wherein the metal chelator is a polyaminocarboxylate chelator or selected from Table 2.
  15. 15 . The compound of claim 12 , wherein the metal chelator is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), N,N′-bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (H 2 -MACROPA), 2,2′,2″,2′″-(1,10-dioxa-4,7,13,16-tetraazacyclooctadecane-4,7,13,16-tetrayl)tetraacetic acid (CROWN), or a derivative thereof.
  16. 16 . The compound of claim 12 , wherein the prosthetic group containing BF 3 is —R 13 R 14 BF 3 wherein R 13 is —(CH 2 ) 1-5 — and —R 14 BF 3 is selected from Table 3 or Table 4 or is wherein each R 15 and each R 16 are independently a branched or linear C 1 -C 5 alkyl.
  17. 17 . The compound of claim 16 , wherein —R 14 BF 3 is
  18. 18 . The compound of claim 17 , wherein R 15 and R 16 are each methyl.
  19. 19 . The compound of claim 12 , wherein the prosthetic group containing BF 3 comprises at least one 18 F.
  20. 20 . The compound of claim 1 , wherein at least one R X is a therapeutic moiety or at least one R X is fluorescent label.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 18/032,680, filed Apr. 19, 2023, which is a U.S. National Stage Application under 35 U.S.C. § 371 of International Application No. PCT/CA2021/051486, filed Oct. 21, 2021, which claims priority to U.S. Provisional Application No. 63/094,839, filed Oct. 21, 2020, the disclosures of which are hereby incorporated by reference in their entireties for all purposes. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY The sequence listing associated with this application is provided in xml format in lieu of a paper copy, and is hereby incorporated by reference into the specification. The xml file, created on May 30, 2024, is named “A9TH_012_02US_SeqList_ST26.xml” and is −3733 bytes. The xml file is being submitted electronically via EFS-Web. FIELD OF INVENTION The present invention relates to novel peptidic compounds, particularly compounds that target CXCR4 for purposes such as imaging and/or therapeutics. BACKGROUND OF THE INVENTION C—X—C chemokine receptor type 4 (CXCR4) is a G protein-coupled transmembrane receptor that is expressed in hematological and immune tissues and systems.1,2 CXCR4 has only one chemokine as a substrate named stromal-derived-factor-1 (SDF-1), also known as CXCL12.3 CXCR4 is aberrantly expressed in a number of important pathologies that involve inflammation and immune cell trafficking, including athersclerosis,4 systemic erythematous lupus5,6, cancer and others. Importantly, CXCR4 has been found to play key roles in tumourigenesis, chemoresistance and metastasis and its expression has been detected in more than twenty different subtypes of cancers with an accompanying negative prognosis.7-12 As such, there is a need for non-invasive in vivo molecular probes to image CXCR4-expressing tumours for better detection, staging and monitoring of aggressive cancers.13-16 Such imaging agents enable the rapid assessment of patients for expression of specific biomarkers without the need for invasive biopsy procedures that may not always properly capture the heterogeneity of a patient's disease. Furthermore, with the largely poor efficacy of CXCR4 inhibitors in clinical trials, an alternative strategy is to couple the inhibitor with a radiotherapeutic isotope to deliver ionizing β, α, or auger electrons to the sites of the disease. LY2510924 (cyclo[Phe-Tyr-Lys(iPr)-D-Arg-2-Nal-Gly-D-Glu]-Lys(iPr)-NH2) is a cyclic peptide that is reported to block SDF-1α binding to CXCR4 with an IC50 value of 79 pM17. It was reported that LY2510924 was able to inhibit growth of non-Hodgkin lymphoma, renal cell carcinoma, lung cancer, colorectal cancer, and breast cancer xenograft models. LY2510924 failed to improve treatment efficacy of carboplatin/etoposide chemotherapy for small cell lung cancer patients18. Many CXCR4 peptide-based inhibitors rely on key amino acid residues that include 1) one or more cationic charged side chain residues to make contact with several anionic residues present on the CXCR4 pocket, 2) a tyrosine residue and 3) a naphthalene-based unnatural amino acid in order to maintain good binding affinity with CXCR4.19 This is exemplified in the development of T140, which systematically substituted out each amino acid of a prototype peptide (T22) based on a natural peptide with HIV inhibitory activity via CXCR4 antagonism.19 This has resulted in a number of strong antagonists to CXCR4, including FC131 (which was later repurposed as Pentixafor and Pentixather for imaging and radionuclide therapeutic purposes, respectively) and LY2510924 for radiotheranostic purposes.20 There is therefore an unmet need in the field for improved CXCR4-targeting compounds, e.g. imaging and therapeutic agents for in-vivo diagnosis and treatment, respectively, of diseases/disorders characterized by expression of CXCR4. No admission is necessarily intended, nor should it be construed, that any of the preceding information constitutes prior art against the present invention. SUMMARY OF THE DISCLOSURE The present disclosure relates to compounds useful as imaging agents and/or therapeutic agents. In some embodiments, the compound of the present disclosure relates to a compound of Formula A, Formula B, or Formula C, or a salt or solvate thereof: wherein: R2a is —(CH2)—(R2b)-(phenyl), wherein R2b is absent, —CH2—, —NH—, —S— or —O—, wherein the phenyl is optionally 4-substituted with —NH2, —NO2, —OH, —OR2c, —SH, —SR2c, or —O-phenyl, wherein the phenyl is optionally 3-substituted with halogen or —OH, wherein the phenyl is optionally 5-subsituted with halogen or —OH, wherein the —O-phenyl ring is optionally 4-substituted with —NH2, —NO2, —OH, —OR2c, —SH, or —SR2c, wherein the —O-phenyl ring is optionally 3-substituted with halogen or —OH, wherein the —O-phenyl ring is optionally 5-subsituted with halogen or —OH, wherein each R2c is independently a C1-C3 linear or branched alkyl group;R3a is R3bR3c wherein R3b is a linea