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CN-122029186-A - Human growth hormone receptor antagonists and methods of use thereof

CN122029186ACN 122029186 ACN122029186 ACN 122029186ACN-122029186-A

Abstract

Described herein are growth hormone receptor antagonists and modified growth hormone receptor antagonists. The growth hormone receptor antagonists and the modified growth hormone receptor antagonists are useful for treating diseases or conditions responsive to human growth hormone receptor antagonists, such as cancer and acromegaly.

Inventors

  • Laura Moscowic
  • Amit rivitz
  • Ahua Bar Ilan
  • Moran Golan
  • Mili Ge'erzong Zakar
  • Avi Neznanski

Assignees

  • OPKO生物科学有限公司

Dates

Publication Date
20260512
Application Date
20241022
Priority Date
20231024

Claims (20)

  1. 1. A human growth hormone receptor antagonist ("GHR antagonist" or "hGHA") comprising the growth hormone receptor antagonist G120K (SEQ ID NO: 2) and at least one of the following amino acid mutations H18D, H21N, F P, R64K, R167N, D171S, E174S, I T.
  2. 2. The GHR antagonist of claim 1, further comprising at least one amino acid mutation to cysteine, and wherein the amino acid mutated to cysteine is T3, E39, P48, Q69, N99, L129, T135, T142, H151, or a combination thereof.
  3. 3. The GHR antagonist of claim 1, wherein the GHR antagonist has the following amino acid mutations: (a) G120K, L129C, R167N, D171S, E S and I179T; (b) H18D, H21N, F P, R64K, G K, L129C, R167N, D171S, E S and I179T; (c) H18D, H, N, G, K, L, 129C, R, 167N, D, 171S, E S and I179T; or (D) H18D, H, 21N, G, K, T, C, R, 167, N, D, 171, S, E S and I179T.
  4. 4. A GHR antagonist as claimed in claim 3, wherein the GHR antagonist comprises the amino acid sequence of SEQ ID No. 5, SEQ ID No. 6, SEQ ID No. 7 or SEQ ID No. 8.
  5. 5. A modified human growth hormone receptor antagonist ("modified GHR antagonist" or "modified hGHA") having the structure of formula (I): W-X-Y-Z(I) Wherein: W represents a conjugate; x represents a spacer; Y represents an optional linker; Z represents a human growth hormone receptor antagonist ("GHR antagonist"); Or a pharmaceutically acceptable salt thereof.
  6. 6. The modified GHR antagonist of claim 5, wherein the GHR antagonist comprises any of the claims 1-4.
  7. 7. A modified GHR antagonist as claimed in any of claims 5 to 6, wherein W is a fatty acid.
  8. 8. The modified GHR antagonist of any of claims 5-6, wherein W is octadecanedioic acid (C18 diacid) or eicosanedioic acid (C20 diacid).
  9. 9. The modified GHR antagonist of claim 8, wherein the octadecanedioic acid (C18 diacid) is represented by formula II: , Or represented by formula II-A: Either (or) or (b) Wherein eicosadioic acid (C20 diacid) and is represented by formula III: ; or by formula III-A: 。
  10. 10. The modified GHR antagonist of any of claims 5-9, wherein X is gGlu-Glu n -(AEEA) m -Cys-Gly p 、gGlu-Glu n -(AEEA) m -Lys(AcBr)-Gly p or Glu-Glu n -(AEEA) m -Lys-Gly p , and n is 1, 2, or 3, m is 1, 2, or 3, and p is 1, 2, or 3.
  11. 11. The modified GHR antagonist of any of claims 5-9, wherein X is Glu- (AEEA) m -Cys-Gly, m is 1,2, or 3, and is represented by formula IV: ; Or by the formula IV-E; 。
  12. 12. The modified GHR antagonist of any of claims 5-9, wherein X is Glu- (AEEA) m -Lys (AcBr) -Gly, m is 1,2, or 3, and is represented by formula V: ; Or by the formula V-C: 。
  13. 13. The modified GHR antagonist of any of claims 5-9, wherein X is Glu- (AEEA) m -Lys-Gly, m is 1, 2, or 3, and is represented by formula VI: ; Or by formula VI-C: 。
  14. 14. A modified GHR antagonist as claimed in any of claims 5 to 13 wherein Y is chloropropane-2-one-Fmoc-Mal.
  15. 15. The modified GHR antagonist of claim 14, wherein chloropropane-2-one-Fmoc-Mal is represented by formula VII: ; or by formula VII-C: 。
  16. 16. A modified GHR antagonist as claimed in any of claims 5 to 13 wherein Y is Mal-NRFmoc-NHS.
  17. 17. The modified GHR antagonist of claim 16, wherein Mal-NRFmoc-NHS is represented by formula X: ; or by the formula X-C: 。
  18. 18. the modified GHR antagonist of any of claims 16-17, wherein the bond between the GHR antagonist and the linker is a stable covalent bond.
  19. 19. The modified GHR antagonist of any of claims 14-15, wherein the bond between the GHR antagonist and the linker is a reversible covalent bond.
  20. 20. The modified GHR antagonist of any of claims 5-19, wherein the modified GHR antagonist comprises any of the following formulas: (formula XV); (formula XVI); (formula XVII); (formula XVIII); (formula XIX); (formula XX); (formula XXI); (formula XXII); (formula XXIII); (formula XXIV); (formula XXV); (formula XXVI); (formula XXVII); (formula XXVIII); (formula XXIX), or (Formula XXX).

Description

Human growth hormone receptor antagonists and methods of use thereof Cross Reference to Related Applications The present application claims the benefit of U.S. provisional application Ser. No. 63/592,760, filed on 10/24 of 2023, which is incorporated herein by reference in its entirety. Sequence listing The sequence listing conforming to the rule of WIPO standard st.26 is hereby incorporated by reference. The application contains a sequence table that has been submitted electronically in an XML file format. The electronic document created at 10/14 of 2024 is entitled "P-625439-pc_st26.xml" and has a size of 12,680 bytes. Technical Field Described herein are growth hormone receptor antagonists and modified growth hormone receptor antagonists. The growth hormone receptor antagonists and the modified growth hormone receptor antagonists are useful for treating diseases or conditions responsive to human growth hormone receptor antagonists, such as cancer and acromegaly. Background The described invention relates generally to compositions useful as receptor antagonists, and more particularly to human growth hormone antagonists having the potential to be highly potent therapeutic agents. Human growth hormone, also known as auxin or somatotropin, is a peptide hormone that stimulates growth, cell proliferation and regeneration in humans and other animals. Growth hormone is a class of mitogens that are specific for only certain types of cells and is a 191 amino acid single chain polypeptide synthesized, stored and secreted by somatotrophic hormone cells in the lateral wings of the anterior pituitary. Receptors are protein molecules that are typically found embedded within the plasma membrane surface of cells, which receive chemical signals from outside the cell. When such chemical signals bind to a receptor, the chemical signals elicit some form of cellular/tissue response, e.g., a change in the electrical activity of the cell. In this sense, a receptor is a protein molecule that recognizes and responds to an endogenous chemical signal. Agonists (e.g., human growth hormone) are chemical compositions that bind to and activate a receptor to produce a biological response. While agonists cause action, antagonists block the action of the agonist, and inverse agonists cause an action opposite to that of the agonist. Receptor antagonists are a class of receptor ligands or drugs that block or inhibit agonist-mediated responses, rather than elicit a biological response itself upon binding to a receptor. These compositions are sometimes referred to as blockers and examples include alpha blockers, beta blockers, and calcium channel blockers. In pharmacology, antagonists have affinity but no efficacy at their cognate receptors, and binding will disrupt interactions and inhibit the function of the agonist or inverse agonist at the receptor. Antagonists bind to the receptor by mediating its action by binding to active (orthosteric) or other (allosteric) sites on the receptor, or the antagonists may interact at unique binding sites that are not normally involved in the biological regulation of the activity of the receptor. Antagonist activity may be reversible or irreversible, depending on the lifetime of the antagonist-receptor complex, which in turn depends on the nature of the antagonist-receptor binding. Most drug antagonists achieve their efficacy by competing with endogenous ligands or substrates at structurally defined binding sites on the receptor. By definition, an antagonist does not exhibit the efficacy of activating its bound receptor, and the antagonist does not maintain the ability to activate the receptor. Once bound, however, antagonists inhibit the function of agonists, inverse agonists and partial agonists. Acromegaly is a syndrome that occurs when the anterior pituitary lobe produces excess human growth hormone (hGH) after pubertal epiphyseal closure. If hGH is overproduced prior to epiphyseal closing, then the result is giant (or megaly) disorder. Many disorders may increase hGH output of the pituitary, although the most common are those involving tumors known as pituitary adenomas, which are derived from different types of cells (growth hormone). Acromegaly affects middle-aged adults most commonly, and if untreated, can lead to severe disfigurement, complications, and premature death. Due to its slow pathogenesis and progression, the disease is difficult to diagnose at an early stage and often misses for many years until changes in external features (particularly the face) become apparent. Acromegaly is a rare endocrine condition caused by hypersecretion of Growth Hormone (GH). The clinical effects resulting therefrom are attributable to the high serum concentrations of both GH and GH-dependent insulin-like growth factor-1 (IGF-1). GH antagonists are useful in treating acromegaly in patients who exhibit inadequate response to surgery and/or radiation therapy, as well as other medical therapies, or who are unsui