Using inhibitors of histone deacetylases for the suppression therapy of inherited disease predisposing conditions

Abstract

Compounds can be used to act as inhibitors of enzymes having histone deacetylase activity for the medical therapy of conditions which predispose a person for the development of a disease, such as but not limited to cancer, inflammatory or metabolic diseases. Such conditions are linked to genetically inherited mutations of crucial genes which predispose a person with this condition to develop the disease phenotype. Thus, such compounds can be used for a suppressive therapeutic approach—the SUPPRESSION THERAPY—in order to inhibit or delay the onset or progression of the genetically predisposed disorder. Furthermore, a clinically used medicament can be manufactured for the SUPPRESSION THERAPY of such inherited predisposing conditions.

1 . A method of treating a person having an inherited condition which predisposes the person for the development of a disease, the method comprising:
 administering a medicament comprising an histone deacetylase inhibitor to the person.   
     
     
         2 . The method according to  claim 1 , wherein the inherited condition is based on at least one genetically inherited mutation of at least one gene, which predisposes a person to develop the disease phenotype. 
     
     
         3 . The method according to  claim 1 , wherein the inherited condition is based on a genetically inherited polymorphism of at least one gene which predisposes a person with his/her condition to develop the disease phenotype. 
     
     
         4 . The method according to  claim 1 , wherein the inherited condition is a predisposing disorder in which the induction of hyperacetylation of histones, of other proteins, or of both, has a beneficial therapeutic effect for patients. 
     
     
         5 . The method according to  claim 1 , wherein the inherited condition is a disease predisposing condition selected from the group consisting of Li-Fraumeni Syndrome, Familial Retinoblastoma, Wilms Tumor, Neurofibromatosis Type 1, Neurofibromatosis Type 2, Tuberous sclerosis 1, Tuberous sclerosis 2, Deleted in Pancreatic Carcinoma 4, Deleted in Colorectal Carcinoma, Gardner's syndrome, Turcot syndrome, Familial Breast Cancer, Peutz-Jeghers Syndrome, Hereditary Nonpolyposis Colorectal Cancer type 1 (HNPCC1), Hereditary Nonpolyposis Colorectal Cancer type 2 (HNPCC2), von Hippel-Lindau Syndrome, Familial Melanoma, Gorlin Syndrome, MYH-associated polyposis, Nevoid basal cell carcinoma syndrome (NBCCS), Multiple Endocrine Neoplasia Type 1, Multiple Endocrine Neoplasia Type 2, Beckwith-Wiedmann Syndrome, Hereditary papillary renal cancer (HPRC), Cowden syndrome, Hereditary prostate cancer, Ataxia telangiectasia, Bloom syndrome, Xeroderma pigmentosum, Fanconi's anemia, PTEN hamartoma tumor syndrome, and juvenile polyposis syndrome. 
     
     
         6 . The method according to  claim 1 , wherein the inherited condition is based on a mutation or polymorphism in a gene selected from the group consisting of p53, pRB 1, WT1, NF1, NF2, APC, TSC1, TSC2, DPC4, Smad4, DCC, BRCA1, BRCA2, STK11, MSH2, MLH1, VHL, CDKN2A, PTCH, MEN1, RET, MEN2, MYH, p57, KIP2, MET, beta-catenin, PTEN, HPC1, PRCA1, ATM, BLM, XPA-XPG, FANCA-FANCH, HPC1, PRCA1, HPCX, MXI1, KAI1, and PCAP. 
     
     
         7 . The method according to any  claim 1 , wherein the inherited condition is a disease predisposing condition selected from the group consisting of Asthma, Atopic dermatitis, Psoriasis, Insulin-dependent Diabetes Mellitus, non-insulin-dependent Diabetes Mellitus, Maturity-onset Diabetes, Graves disease, Autoimmune Polyendocrinopathy Syndrome, Chrohn's disease, Inflammatory bowel disease, Inflammatory demyelinating polyneuropathy, Guillain-Barre-Syndrome, multiple and recurrent inflammatory fibroid polyps, neovascular inflammatory vitreoretinopathy, chronic neurologic cutaneous and articular syndrome, CINCA Syndrome, hereditary inflammatory vasculitis, familial recurrent arthritis, autosomal dominant familial peroidic fever, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, multiple sclerosis, hereditary myopathy, hereditary muscular dystrophy, Ankylosis Spondylitis, Bechterew Syndrome, Lupus Erythematosus, and Osteomylitis. 
     
     
         8 . The method according to  claim 1 , wherein the inherited condition is based on a mutation or polymorphism in at least one gene locus selected from the group consisting of IL13, ALRH, BHR1, SCGB3A2, UGRP1, PLA2G7, PAFAH, PHF11, NYREN34, ATOD1, ATOD6, ATPD5, ATOD4, ATOD3 PSORS9, PSORS7, PSORS6, PSORS5, PSORS4, PSORS3, PSORS2, PSORS1, PSS1, IDDM1, TCF1, HNF1A, MODY3, Interferon production regulator factor (HNF1), albumin proximal factor, FOXP3, IPEX, AIID, XPID, PIDX Forkhead box P3 (scurfin), HLA, properdin factor B, glyoxalase-1, Kidd blood group, HLA-DQ(beta), GPD2, NEUROD1, NIDDM, CAPN10, Calpain-10, VEGF, MAPK8IP1, IB 1, TCF1, HNF1A, MODY3, Interferon production regulator factor, albumin proximal factor, IPF1, IRS2, TCF2, HNF2, LF-B3, GCGR, HNF4A, TCF14, MODY1, NIDDM2, NIDDM3, Glut 2, Glut 4, GPD2, AIRE, APECED, IBD7, IBD9, IBD5, IBD3, IBD2, IBD4, IBD8, IBD6, CARD15, NOD2, ABCB1, DLG5, SLC22A4, SLC22A5, IBD1, CD, ACUG, NOD2, PMP22, GAS3, VRNI, D11S527, CIAS1, Clorf7, FCU, FCAS, AS, ANS, Major histocompatibility complex class I B, HLA-B27, FCGR3A, FCGR2A, CD16, IGFR3, TNFSF6, APT1LG1, FAS, FASL, TNFRSF1A, TNFA, PSTPIP1, PTPRC, CD45, HLA-A3, HLA-B7, HLA-Dw2, CRYAB, Immuneglobuline KM1/3, SLEB1, SLE1, PDCD1, SLEB2, SLEB3, SLEH1, SLEB4, DNAse1, SLEV1, SLEN1, SLEN2, and SLEN3. 
     
     
         9 . The method according to  claim 1 , wherein the treatment of the inherited condition comprises SUPPRESSION THERAPY of an inherited predisposition. 
     
     
         10 . The method according to  claim 1 , wherein the histone deacetylase inhibitor is 2-propyl-pentanoic acid or a pharmaceutical acceptable salt thereof. 
     
     
         11 . The method according to  claim 1 , wherein the histone deacetylase inhibitor is selected from the group consisting of hydroxamic acid derivatives, benzamides, pyroxamides and derivatives thereof, microbial metabolites exhibiting HDAC inhibitory activity, fatty acids and derivatives thereof, cyclic tetrapeptides, peptidic compounds, HDAC class III inhibitors, and SIRT inhibitors. 
     
     
         12 . The method according to  claim 1 , wherein the inhibitor of histone deacetylases is selected from the group consisting of hydroxamic acid derivatives such as NVP-LAQ824, Trichostatin A (TSA), Suberoyl anilide hydroxamic acid, CBHA, G2M-701, G2M-702, G2M-707, Pyroxamide, Scriptaid, CI-994, CG-1521, Chlamydocin, Biaryl hydroxamate, A-161906, Bicyclic aryl-N-hydroxycarboxamides, PXD-101, Sulfonamide hydroxamic acid, TPX-HA analogue (CHAP), Oxamflatin, Trapoxin, Depudecin, Apidicin, benzamides, MS-27-27, butyric acid and derivatives thereof, Pivanex (Pivaloyloxymethyl butyrate), trapoxin A, Depsipeptide (FK-228) and related peptidic compounds, Tacedinaline, and MG2856. 
     
     
         13 . The method according to  claim 1 , wherein the histone deacetylase inhibitor is a compound of formula I 
       
         
           
           
               
               
           
         
       
       wherein R 1  and R 2  independently are a linear or branched, saturated or unsaturated, aliphatic C 3-25  hydrocarbon chain which optionally comprises one or several heteroatoms and which may be substituted, R 3  is hydroxyl, halogen, alkoxy or an optionally alkylated amino group, or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The method according to  claim 13 , wherein R 1  and R 2  independently are a linear or branched C 3-25  hydrocarbon chain which optionally comprises one double or triple bond. 
     
     
         15 . The method according to  claim 1 , wherein administering comprises intraveneous, intramuscular, subcutaneous, topical, oral, nasal, intraperitoneal, or suppository based administering. 
     
     
         16 . A method of using a histone deacetylase inhibitor as a medicament for the treatment or prevention of an inherited disease, the method comprising:
 administering the medicament to an individual having an inherited condition predisposing him/her for the development of the inherited disease.   
     
     
         17 . The method according to  claim 16 . wherein the inherited condition is an inherited condition selected from the group consisting of:
 an inherited condition based on at least one genetically inherited mutation of at least one gene, which predisposes a person to develop the disease phenotype;   an inherited condition based on a genetically inherited polymorphism of at least one gene which predisposes a person with his/her condition to develop the disease phenotype;   an inherited condition which is a predisposing disorder in which the induction of hyperacetylation of histones, of other proteins, or of both, has a beneficial therapeutic effect for patients;   a disease predisposing condition selected from the group consisting of Li-Fraumeni Syndrome, Familial Retinoblastoma, Wilms Tumor, Neurofibromatosis Type 1, Neurofibromatosis Type 2, Tuberous sclerosis 1, Tuberous sclerosis 2, Deleted in Pancreatic Carcinoma 4, Deleted in Colorectal Carcinoma, Gardner's syndrome, Turcot syndrome, Familial Breast Cancer, Peutz-Jeghers Syndrome, Hereditary Nonpolyposis Colorectal Cancer type 1 (HNPCC1), Hereditary Nonpolyposis Colorectal Cancer type 2 (HNPCC2), von Hippel-Lindau Syndrome, Familial Melanoma, Gorlin Syndrome, MYH-associated polyposis, Nevoid basal cell carcinoma syndrome (NBCCS), Multiple Endocrine Neoplasia Type 1, Multiple Endocrine Neoplasia Type 2, Beckwith-Wiedmann Syndrome, Hereditary papillary renal cancer (HPRC), Cowden syndrome, Hereditary prostate cancer, Ataxia telangiectasia, Bloom syndrome, Xeroderma pigmentosum, Fanconi's anemia, PTEN hamartoma tumor syndrome, and juvenile polyposis syndrome;   an inherited condition based on a mutation or polymorphism in a gene selected from the group consisting of p53, pRB1, WT1, NF1, NF2, APC, TSC1, TSC2, DPC4, Smad4, DCC, BRCA1, BRCA2, STK11, MSH2, MLH1, VHL, CDKN2A, PTCH, MEN1, RET, MEN2, MYH, p57, KIP2, MET, beta-catenin, PTEN, HPC1, PRCA1, ATM, BLM, XPA-XPG, FANCA-FANCH, HPC1, PRCA1, HPCX, MXI1, KAI1, and PCAP;   a disease predisposing condition selected from the group consisting of Asthma, Atopic dermatitis, Psoriasis, Insulin-dependent Diabetes Mellitus, non-insulin-dependent Diabetes Mellitus, Maturity-onset Diabetes, Graves disease, Autoimmune Polyendocrinopathy Syndrome, Chrohn's disease, Inflammatory bowel disease, Inflammatory demyelinating polyneuropathy, Guillain-Barre-Syndrome, multiple and recurrent inflammatory fibroid polyps, neovascular inflammatory vitreoretinopathy, chronic neurologic cutaneous and articular syndrome, CINCA Syndrome, hereditary inflammatory vasculitis, familial recurrent arthritis, autosomal dominant familial peroidic fever, familial cold autoinflammatory syndrome, Muckle-Wells syndrome, multiple sclerosis, hereditary myopathy, hereditary muscular dystrophy, Ankylosis Spondylitis, Bechterew Syndrome, Lupus Erythematosus, and Osteomylitis; and   an inherited condition based on a mutation or polymorphism in at least one gene locus selected from the group consisting of IL13, ALRH, BHR1, SCGB3A2, UGRP1, PLA2G7, PAFAH, PHF11, NYREN34, ATOD1, ATOD6, ATPD5, ATOD4, ATOD3 PSORS9, PSORS7, PSORS6, PSORS5, PSORS4, PSORS3, PSORS2, PSORS1, PSS1, IDDM1, TCF1, HNF1A, MODY3, Interferon production regulator factor (HNF1), albumin proximal factor, FOXP3, IPEX, AIID, XPID, PIDX Forkhead box P3 (scurfin), HLA, properdin factor B, glyoxalase-1, Kidd blood group, HLA-DQ(beta), GPD2, NEUROD1, NIDDM, CAPN10, Calpain-10, VEGF, MAPK8IP1, IB1, TCF1, HNF1A, MODY3, Interferon production regulator factor, albumin proximal factor, IPF1, IRS2, TCF2, HNF2, LF-B3, GCGR, HNF4A, TCF14, MODY1, NIDDM2, NIDDM3, Glut 2, Glut 4, GPD2, AIRE, APECED, IBD7, IBD9, IBD5, IBD3, IBD2, IBD4, IBD8, IBD6, CARD15, NOD2, ABCB1, DLG5, SLC22A4, SLC22A5, IBD1, CD, ACUG, NOD2, PMP22, GAS3, VRNI, D11S527, CIAS1, Clorf7, FCU, FCAS, AS, ANS, Major histocompatibility complex class I B, HLA-B27, FCGR3A, FCGR2A, CD16, IGFR3, TNFSF6, APT1LG1, FAS, FASL, TNFRSF1A, TNFA, PSTPIP1, PTPRC, CD45, HLA-A3, HLA-B7, HLA-Dw2, CRYAB, Immuneglobuline KM1/3, SLEB1, SLE1, PDCD1, SLEB2, SLEB3, SLEH1, SLEB4, DNAse1, SLEV1, SLEN1, SLEN2, and SLEN3.