Epidermal growth factor receptor inhibitors

Abstract

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

Description

This disclosure relates in general to epidermal growth factor receptor (EGFR) inhibitors and methods for treating EGFR-dependent or related diseases, conditions, or illnesses, such as cancer. Abstract

Claims

CLAIMS:

1. A cyclic peptide comprising the sequence of the formula: Xaa1- Xaa2- Xaa3- Xaa4- Xaa5in which: Xaa1is F or 1NapA; Xaa2is L or I; Xaa3is S or T; Xaa4is F or 2NapA; and Xaa5is R or K.

2. The cyclic peptide of Claim 1, wherein: (a) Xaa1is 1NapA and Xaa4is 2NapA; (b) Xaa1is F and Xaa4is 2NapA; (c) Xaa1is F and Xaa4is F; or (d) Xaa1is 1NapA and Xaa4is F.

3. A cyclic peptide comprising the sequence of Formula I, or a pharmaceutically acceptable salt, solvate or prodrug thereof:Formula I wherein: Xaa1is selected from 1-naphthyl-alanine and phenylalanine; and Xaa2is selected from 2-naphthyl-alanine and phenylalanine.

4. The cyclic peptide of any one of the preceding claims, comprising the sequence of: (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. The cyclic peptide of any one of the preceding claims, comprising the chemical structure of: (a)(cyclo[(D-Phe)LS(L-Phe)R]); or a pharmaceutically acceptable salt, solvate or prodrug thereof.

6. The cyclic peptide of any one of the preceding claims, wherein the cyclic peptide is in the form of an acetate salt.

7. A pharmaceutical composition, comprising the cyclic peptide of any one of the preceding claims and a pharmaceutically acceptable carrier, diluent or excipient.

8. A method of treating, preventing or ameliorating an EGFR-related disease, disorder or condition in a subject, said method including 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 thereby treat, prevent or ameliorate the EGFR-related disease, disorder or condition.

9. The method of Claim 8, wherein the EGFR-related disease, disorder or condition is an EGFR-related cancer.

10. The method of Claim 9, wherein 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, gliosarcoma, colorectal cancer, breast cancer, oesophageal cancer, bladder cancer, hepatocellular carcinoma, renal cell carcinoma, brain and central nervous system cancer, neuroendocrine cancer, lymphoma, multiple myeloma, or chronic lymphocytic leukaemia.

11. A method of inhibiting EGFR in a cell, said method including 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 thereby inhibit EGFR in the cell.

12. A method of promoting internalisation and / or lysosomal degradation of EGFR in a cell, said method including 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 thereby promote internalisation and / or lysosomal degradation of EGFR in the cell.

13. The method of Claim 11 or Claim 12, wherein the cell is a cancer cell.

14. A method of reducing the viability and / or growth of a cancer cell, said method including the step of contacting the cancer cell with an effective amount of the cyclic peptide of any one ofClaims 1 to 6 or the pharmaceutical composition of Claim 7 to thereby reduce the viability and / or growth of the cancer cell.

15. The method of Claim 13 or Claim 14, wherein the cancer cell is a prostate cancer cell, a non-small cell lung cancer cell, a pancreatic cancer cell, an ovarian cancer cell, a gastrointestinal cancer cell, a rectal cancer cell, a kidney cancer cell, a liver cancer cell, a gallbladder cancer cell, a head and neck cancer cell, a transitional cell carcinoma cell, a squamous cell carcinoma cell, a melanoma cell, a glioblastoma cell, a gliosarcoma cell, a colorectal cancer cell, a breast cancer cell, an oesophageal cancer cell, a bladder cancer cell, a hepatocellular carcinoma cell, a renal cell carcinoma cell, a brain and central nervous system cancer cell, a neuroendocrine cancer cell, a lymphoma cell, a multiple myeloma cell, or a chronic lymphocytic leukaemia cell.

16. The method of any one of Claims 13 to 15, wherein the cancer cell is an EGFR-related cancer cell.

17. Use of the cyclic peptide of any one of Claims 1 to 6 or the pharmaceutical composition of Claim 7 in the manufacture of a medicament for use in therapy.

18. Use of the cyclic peptide of any one of Claims 1 to 6 or the pharmaceutical composition of Claim 7 in the manufacture of a medicament for treating, preventing or ameliorating an EGFR- related disease, disorder or condition.

19. The cyclic peptide of any one of Claims 1 to 6 or the pharmaceutical composition of Claim 7 for use in therapy.

20. The cyclic peptide of any one of Claims 1 to 6 or the pharmaceutical composition of Claim 7 for use in treating, preventing or ameliorating an EGFR-related disease, disorder or condition.

21. A method of identifying, designing or producing an agent capable of interacting with or binding to a ligand binding domain of EGFR, said method including the steps of: (a) contacting a cell expressing EGFR with a candidate agent, wherein the candidate agent is a derivative, variant or analogue of: (i) cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg); or (ii) the cyclic peptide of any one of Claims 1 to 6; and(b) determining whether the candidate agent inhibits the binding of an EGFR ligand to EGFR of the cell.

22. The method of Claim 21, wherein the EGFR ligand is EGF or hGIIA.

23. The method of Claim 21 or Claim 22, wherein the ligand binding domain of EGFR comprises or is defined by one or more residues selected from amino acids Q8, G9, T10, S11, N12, K13, L14, T15, Q16, L17, H23, F24, L25, S26, L27, Q28, R29, M30, L41, E42, I43 and T44 of SEQ ID NO:

2.

24. The method of any one of Claims 21 to 23, further including the step of determining whether the candidate agent promotes lysosomal degradation of EGFR in the cell.

25. The method of any one of Claims 21 to 24, further including the step of isolating and / or purifying an agent that inhibits the binding of the EGFR ligand to EGFR.

26. The method of Claim 25, further including the step of formulating the isolated and / or purified agent into a pharmaceutically acceptable formulation.

27. The method of Claim 26, further including the step of sterilising the formulation.

28. The method of Claim 26 or Claim 27, further including the step of filling the formulation into a container.

29. The method of Claim 28, wherein the container is any one or more of a vial, an ampoule, a bag, a blister pack, a bottle, a cartridge, an injection needle, an injection syringe, a single dose container, a strip of multiple single dose containers, or a tube.

30. An agent capable of interacting with or binding to a ligand binding domain of EGFR, obtained by the method of any one of Claims 21 to 29.

31. A method of manufacturing the cyclic peptide of any one of Claims 1 to 6, wherein said method comprises solid phase synthesis.

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