N- and C-terminal substituted antagonistic analogs of GH-RH
Inventors
Schally, Andrew V. • Zarandi, Marta • Varga, Jozsef L. • Cai, Ren Zhi
Assignees
University of Miami • US Department of Veterans Affairs
Publication Number
US-9260504-B2
Publication Date
2016-02-16
Expiration Date
2029-03-26
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Abstract
There is provided a novel series of synthetic analogs of hGH-RH(1-29)NH2 (SEQ ID NO: 1) and hGH-RH(1-30)NH2. Of particular interest are those carrying PhAc, N-Me-Aib, Dca, Ac-Ada, Fer, Ac-Amc, Me-NH-Sub, PhAc-Ada, Ac-Ada-D-Phe, Ac-Ada-Phe, Dca-Ada, Dca-Amc, Nac-Ada, Ada-Ada, or CH3—(CH2)10—CO-Ada, at the N-Terminus and β-Ala, Amc, Apa, Ada, AE2A, AE4P, ε-Lys(α-NH2), Agm, Lys(Oct) or Ahx, at the C-terminus. These analogs inhibit the release of growth hormone from the pituitary in mammals as well as inhibit the proliferation of human cancers, and inhibit the hyperplastic and benign proliferative disorders of various organs, through a direct effect on the cancerous and non-malignant cells. The stronger inhibitory potencies of the new analogs, as compared to previously described ones, result from replacement of various amino acids.
Core Innovation
There is provided a novel series of synthetic analogs of human growth hormone-releasing hormone (hGH-RH) fragments hGH-RH(1-29)NH2 and hGH-RH(1-30)NH2. These synthetic analogs carry specific substitutions primarily at their N- and C-terminal residues and are designed to inhibit the release of growth hormone from the pituitary in mammals. Moreover, these analogs inhibit the proliferation of human cancers and hyperplastic and benign proliferative disorders in various organs through direct effects on both cancerous and non-malignant cells.
The problem being addressed is the need for more potent GH-RH antagonists that not only act at the pituitary level to inhibit growth hormone release but also exert strong direct inhibitory effects on tumor cells. Existing GH-RH antagonists may suppress GH and IGF-I levels but often lack sufficient potency or specificity for direct tumor growth inhibition. Additionally, prior analogs predominantly targeted pituitary receptors without full characterization of effects on tumoral GH-RH receptors or the structural features necessary for such antagonism.
Claims Coverage
The patent includes several independent claims directed to synthetic GHRH peptide analogs and pharmaceutical compositions comprising these peptides. The main inventive features relate to specific peptide structures and their pharmaceutical formulations.
Specific substituted GHRH peptide analogs with defined residues at key positions
The invention claims GHRH peptides of a defined formula featuring specific substitutions at the N-terminus (e.g., PhAc-Ada), positions 1 to 30 of the peptide sequence including substitutions such as D-Arginine at position 2, various amino acid or analog replacements at position 8 (Ala or Me-Ala), and agmatine (Agm) at the C-terminus position 30. The peptides exhibit antagonistic activity against GH-RH by inhibiting growth hormone release and tumor growth.
Peptides with substitutions at position 8 as Ala or Me-Ala
An inventive feature involves peptides wherein residue 8 is either alanine (Ala) or N-methyl-alanine (Me-Ala), which modulates antagonistic activity while maintaining or improving tumor inhibitory efficacy.
Pharmaceutical compositions comprising the defined GHRH peptides or their salts
The claims cover pharmaceutical compositions comprising the peptides or their pharmaceutically acceptable salts, formulated for therapeutic use, including injections and compositions for tumor growth inhibition and endocrine modulation.
The claims provide coverage of novel GHRH peptide analogs with specific N- and C-terminal substitutions that yield enhanced antagonistic properties against GH-RH-induced growth hormone release and direct tumor growth inhibition, along with their pharmaceutical compositions.
Stated Advantages
The new analogs demonstrate stronger inhibitory potencies compared to previously described analogs, resulting from targeted replacement of amino acids.
The peptides inhibit the proliferation of human cancers and hyperplastic and benign proliferative disorders through direct effects on cancerous and non-malignant cells.
GH-RH antagonists have multiple mechanisms of action, including endocrine inhibition of GH and IGF-1 levels and direct tumor receptor blockade, resulting in superior therapeutic benefits.
Some antagonists exhibit long duration of action and can be formulated as salts of low solubility, depot forms, or biodegradable polymer microcapsules for extended release.
Documented Applications
Treatment of cancers expressing GH-RH receptors such as lung, prostate, breast, ovary, endometrium, stomach, colon, pancreas, kidney, bone, brain, hepatocellular carcinoma, pancreatic carcinoma, and ovarian carcinoma.
Therapy of endocrine disorders characterized by excessive growth hormone and IGF-1 levels, including acromegaly, diabetic retinopathy, diabetic nephropathy, muscular dystrophy, and autoimmune diseases such as multiple sclerosis.
Treatment of hyperplastic and benign proliferative disorders of various normal organs, including benign prostatic hyperplasia and gynecologic conditions like myoma, endometriosis, and polycystic ovary syndrome.
Use as diagnostic or therapeutic agents via conjugation to radionuclides or chemotherapeutic agents, enabling targeted tumor localization or therapy.
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