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-8691942-B2
Publication Date
2014-04-08
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
The invention provides a novel series of synthetic analogs of hGH-RH(1-29)NH2 and hGH-RH(1-30)NH2. These analogs inhibit the release of growth hormone from the pituitary in mammals and inhibit the proliferation of human cancers, as well as hyperplastic and benign proliferative disorders of various organs, through a direct effect on cancerous and non-malignant cells. The new analogs have stronger inhibitory potencies compared to previously described ones due to the replacement of various amino acids.
The peptides include specific substitutions at the N- and C-termini with diverse residues such as PhAc, N-Me-Aib, Dca, Ac-Ada, and others at the N-terminus, and residues such as β-Ala, Amc, Apa, Ada, and others at the C-terminus. Pharmaceutical compositions containing these novel peptides are also provided for therapeutic use.
The problem being addressed relates to the need for more potent GH-RH antagonists. Although previous GH-RH analogs were known to have agonistic or antagonistic properties on pituitary GH-RH receptors, very little was known about their direct antagonistic effects on tumor cells that express different GH-RH receptors. There was a lack of knowledge about structural features required for direct antagonistic action on tumors and the necessity for improved antagonists that can inhibit growth hormone release and tumor proliferation effectively.
Claims Coverage
The patent contains several independent claims covering the novel synthetic peptides with specific amino acid substitutions that act as GH-RH antagonists with enhanced inhibitory properties.
Peptides with specific N- and C-terminal substitutions of hGH-RH analogs
Peptides selected from groups having specified formulae with defined substitutions at positions A0, A4, A6, A8, Har9, Tyr(Me)10, A11, A12, Abu15, A17, A20, A21, Nle27, D-Arg28, and from A29 to A31 within the hGH-RH(1-29)NH2 sequence, including pharmaceutically acceptable salts.
Specific peptide sequences with defined residue sets for improved antagonistic effect
Peptides with A0 selected from Dca, Ac-Ada, Ac-Amc, PhAc-Ada, Dca-Ada, or CH3—(CH2)10—CO-Ada and A30 as Agm, Ada, or absent, combined with defined amino acid substitutions in the sequence, leading to stronger inhibition of growth hormone release and tumor growth.
Preferred peptides with detailed residue composition impacting activity
Peptides such as [PhAc0-Tyr1, D-Arg2, Cpa6, Ala8, Har9, (Phe(F)5)10, His11, Orn12, Abu15, His20, Orn21, Nle27, D-Arg28, Har29-Ada30]hGH-RH(1-29)NH2 (P-11610) and [(PhAc-Ada)0-Tyr1, D-Arg2, (Phe(F)5)6, Ala8, Har9, Tyr(Me)10, His11, Orn12, Abu15, His20, Orn21, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 (P-11602), including pharmaceutically acceptable salts.
The claims focus on novel synthetic hGH-RH analog peptides with specific N- and C-terminal amino acid substitutions that exhibit enhanced antagonistic activity against growth hormone release and tumor proliferation. These inventive features provide a structural basis for more potent and therapeutically useful GH-RH antagonists.
Stated Advantages
The new analogs have stronger inhibitory potencies compared to previously described GH-RH antagonists, resulting in more effective suppression of growth hormone release and tumor growth.
The peptides provide direct antiproliferative effects on tumor cells by blocking tumoral GH-RH receptors, as well as by lowering serum levels of GH and IGF-1.
The antagonists also reduce the autocrine and paracrine production of tumor growth factors such as IGF-I, IGF-II, VEGF, and FGF, contributing to their antitumor efficacy.
The compounds can be formulated for various pharmaceutical deliveries, including long-acting depot forms, enhancing clinical utility.
Documented Applications
Treatment of human cancers including lung, prostate, breast, ovary, endometrium, stomach, colon, pancreas, kidney, bone, brain, and others expressing GH-RH or related receptors.
Inhibition of hyperplastic and benign proliferative disorders of organs through direct effects on cancerous and non-malignant cells.
Use in endocrine disorders such as acromegaly, diabetic retinopathy, diabetic nephropathy, muscular dystrophy, and gynecological conditions like myoma and endometriosis.
Potential use as carrier systems linked to radionuclides, chemotherapeutic agents, or toxins for tumor localization or therapy.
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