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KR-20260066107-A - Epidermal growth factor receptor inhibitor

KR20260066107AKR 20260066107 AKR20260066107 AKR 20260066107AKR-20260066107-A

Abstract

The present disclosure generally relates to epidermal growth factor receptor (EGFR) inhibitors and methods for treating EGFR-dependent or associated diseases, disorders, or conditions such as cancer.

Inventors

  • 만, 티모시
  • 쩡, 준
  • 스콧, 키어란

Assignees

  • 필라몬 리미티드

Dates

Publication Date
20260512
Application Date
20240904
Priority Date
20230904

Claims (20)

  1. Cyclic peptide comprising the sequence of the following chemical formula: Xaa 1 - Xaa 2 - Xaa 3 - Xaa 4 - Xaa 5 In the above formula, Xaa 1 is F or 1NapA and; Xaa 2 is L or I and; Xaa 3 is S or T and; Xaa 4 is F or 2NapA and; Xaa 5 is R or K.
  2. In paragraph 1, (a) Xaa 1 is 1NapA and Xaa 4 is 2NapA or; (b) Xaa 1 is F and Xaa 4 is 2NapA or; (c) Xaa 1 is F and Xaa 4 is F or; (d) A cyclic peptide in which Xaa 1 is 1NapA and Xaa 4 is F.
  3. A cyclic peptide comprising the sequence of the following chemical formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: In the above formula, Xaa 1 is selected from 1-naphthyl-alanine and phenylalanine; Xaa 2 is selected from 2-naphthyl-alanine and phenylalanine.
  4. A cyclic peptide comprising the following sequence, in any one of claims 1 to 3: (a) (Cyclo[(1-Nal)LS(2-Nal)R]); (b) (Cyclo[(Phe)LS(2-Nal)R]); or (c) (Cyclo[(Phe)LS(Phe)R]); or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  5. A cyclic peptide comprising the following chemical structure, in any one of claims 1 to 4: (a) (Cyclo[(D-1-Nal)LS(L-2-Nal)R]); (b) (Cyclo[(D-Phe)LS(L-2-Nal)R]); or (c) (Cyclo[(D-Phe)LS(L-Phe)R]); or a pharmaceutically acceptable salt, solvate, or prodrug thereof.
  6. A cyclic peptide according to any one of claims 1 to 5, wherein the cyclic peptide is in the form of an acetate salt.
  7. A pharmaceutical composition comprising a cyclic peptide of any one of claims 1 to 6 and a pharmaceutically acceptable carrier, diluent, or excipient.
  8. A method for treating, preventing, or improving an EGFR-related disease, disorder, or pathological condition in a subject, the method comprising the step of administering a therapeutically effective amount of the cyclic peptide of any one of claims 1 to 6 or the pharmaceutical composition of claim 7 to the subject to treat, prevent, or improve the EGFR-related disease, disorder, or pathological condition.
  9. In claim 8, the above EGFR-related disease, disorder, or condition is an EGFR-related cancer, method.
  10. In claim 9, the EGFR-related cancer is prostate cancer, non-small cell lung cancer, pancreatic cancer, ovarian cancer, gastrointestinal cancer, rectal cancer, kidney cancer, liver cancer, gallbladder cancer, head and neck cancer, transitional cell carcinoma, squamous cell carcinoma, melanoma, glioblastoma, neuroadditive tumor, colorectal cancer, breast cancer, esophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine cancer, lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
  11. A method for inhibiting intracellular EGFR, wherein the method comprises the step of inhibiting intracellular EGFR by contacting the cell with an effective amount of the cyclic peptide of any one of claims 1 to 6 or the pharmaceutical composition of claim 7.
  12. A method for promoting the internalization and/or lysosomal degradation of EGFR within a cell, the method comprising the step of contacting the cell with an effective amount of the cyclic peptide of any one of claims 1 to 6 or the pharmaceutical composition of claim 7 to promote the internalization and/or lysosomal degradation of EGFR within the cell.
  13. A method according to claim 11 or 12, wherein the cell is a cancer cell.
  14. A method for reducing the survival rate and/or growth of cancer cells, the method comprising the step of reducing the survival rate and/or growth of cancer cells by contacting said cancer cells with an effective amount of the cyclic peptide of any one of claims 1 to 6 or the pharmaceutical composition of claim 7.
  15. A method according to claim 13 or 14, wherein the cancer cells are prostate cancer cells, non-small cell lung cancer cells, pancreatic cancer cells, ovarian cancer cells, gastrointestinal cancer cells, rectal cancer cells, kidney cancer cells, liver cancer cells, gallbladder cancer cells, head and neck cancer cells, transitional cell carcinoma cells, squamous cell carcinoma cells, melanoma cells, glioblastoma cells, neuroadditive cancer cells, colorectal cancer cells, breast cancer cells, esophageal cancer cells, bladder cancer cells, hepatocellular carcinoma cells, renal cell carcinoma cells, brain and central nervous system cancer cells, neuroendocrine cancer cells, lymphoma cells, multiple myeloma cells, or chronic lymphocytic leukemia cells.
  16. A method according to any one of claims 13 to 15, wherein the cancer cells are EGFR-associated cancer cells.
  17. The use of a cyclic peptide of any one of claims 1 to 6 or a pharmaceutical composition of claim 7 in the manufacture of a medicine for use in therapy.
  18. The use of a cyclic peptide of any one of claims 1 to 6 or a pharmaceutical composition of claim 7 in the manufacture of a medicine for treating, preventing, or improving an EGFR-related disease, disorder, or condition.
  19. A cyclic peptide of any one of claims 1 to 6 or a pharmaceutical composition of claim 7 for use in therapy.
  20. A cyclic peptide of any one of claims 1 to 6 or a pharmaceutical composition of claim 7 for use in treating, preventing, or improving EGFR-related diseases, disorders, or conditions.

Description

Epidermal growth factor receptor inhibitor Cross-reference regarding related applications This application claims priority to Australian provisional patent application No. 2023902843 filed on September 4, 2023, the contents of which are incorporated herein by reference in their entirety. Technology field The present disclosure generally relates to epidermal growth factor receptor (EGFR) inhibitors and methods for treating EGFR-dependent or associated diseases, disorders, or conditions such as cancer. The epidermal growth factor receptor (EGFR) is a 170 kDa transmembrane protein belonging to the ErbB family of tyrosine kinases. 1. EGFR is overexpressed in many types of cancer and is a target for inhibition in the clinical treatment of non-small cell lung cancer (NSCLC), colorectal cancer (CRC), head and neck cancer, and glioblastoma. 2. In normal physiology, EGFR ligands, such as epidermal growth factor (EGF), bind to the extracellular domain of the receptor, which causes EGFR dimerization in conjunction with other EGFRs or any other receptor from the ErbB family. Dimerization initiates signaling generated from the sequestration of EGFR and the phosphorylation of intracellular tyrosine kinases, activation of key RAS/RAF/MEK/ERK and PI3K/AKT pathways, as well as PKC, Src tyrosine kinase, PLCγ, and STAT downstream signaling. 3 . Aberrant activation of these pathways is critical for pathological cell proliferation, growth, and migration in cancer and other EGFR-related diseases. Monoclonal antibodies targeting EGFR, such as cetuximab, block ligand activation and constitute the major class of clinically used inhibitors, primarily for the treatment of head and neck cancer and CRC. Because novel resistance arises from KRAS, BRAF, and NRAS genes leading to abnormal MAPK signaling 5 , cetuximab treatment is limited to a small subset of patients who do not possess KRAS mutations 4. Additionally, resistance can arise from S492R mutations 6 , which inhibit cetuximab binding rather than EGF ligand binding, or lead to ligand-independent activation 7 through mutation. Tyrosine kinase inhibitors (TKIs) are the second major class of EGFR inhibitors clinically used in the treatment of NSCLC. TKIs target the intracellular tyrosine kinase domain of EGFR, but resistance typically develops because this region is genetically unstable and prone to mutations 8 . Therefore, there remains a clinical need for additional EGFR inhibitors that overcome one or more of the problems of prior art inhibitors. summation The present disclosure is based in part on the discovery of a novel class of EGFR inhibitors that bind to the extracellular domain of EGFR and initiate non-clathrin-mediated endocytosis (non-CME) and lysosomal degradation of EGFR protein. The present disclosure provides cyclic peptides having potent and long-lasting inhibitory activity with respect to EGFR expression and signaling. The inventors have also shown that these cyclic peptides have an anticancer effect in vitro. In a first embodiment, the present disclosure provides a cyclic peptide comprising the sequence of the following chemical formula: Xaa 1 - Xaa 2 - Xaa 3 - Xaa 4 - Xaa 5 In the above formula, Xaa 1 is F or 1NapA and; Xaa 2 is L or I and; Xaa 3 is S or T and; Xaa 4 is F or 2NapA and; Xaa 5 is R or K. Suitablely: (a) Xaa 1 is 1NapA and Xaa 4 is 2NapA or; (b) Xaa 1 is F and Xaa 4 is 2NapA or; (c) Xaa 1 is F and Xaa 4 is F or; (d) Xaa 1 is 1NapA and Xaa 4 is F. In a second aspect, the present disclosure provides a cyclic peptide comprising the sequence of the following formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof: In the above formula, Xaa 1 is selected from 1-naphthyl-alanine and phenylalanine; Xaa 2 is selected from 2-naphthyl-alanine and phenylalanine. In a specific example of the above embodiment, the cyclic peptide comprises the following sequence: (a) (Cyclo[(1-Nal)LS(2-Nal)R]); (b) (Cyclo[(Phe)LS(2-Nal)R]); or (c) (Cyclo[(Phe)LS(Phe)R]); or a pharmaceutically acceptable salt, solvate, or prodrug thereof. According to some examples of the aforementioned embodiments, the cyclic peptide comprises the following chemical structure: (a) (Cyclo[(D-1-Nal)LS(L-2-Nal)R]) (D1); (b) (Cyclo[(D-Phe)LS(L-2-Nal)R]) (D2); or (c) (Cyclo[(D-Phe)LS(L-Phe)R]) (D3); or a pharmaceutically acceptable salt, solvate, or prodrug thereof. Suitably, the cyclic peptide of the above embodiment is in the form of an acetate salt. In a third aspect, the present disclosure provides a pharmaceutical composition comprising a cyclic peptide of any one of the prior claims and a pharmaceutically acceptable carrier, diluent, or excipient. Suitably, a cyclic peptide of the first or second embodiment or a pharmaceutical composition of the third embodiment is intended for use in therapy. Suitably, the cyclic peptide of the first or second embodiment or the pharmaceutical composition of the third embodiment is intended for use in treating, preventing, or improving EGFR