COMPOUNDS, COMPOSITIONS, METHODS, AND USES FOR TREATING INSULIN RESISTANCE, TYPE 2 DIABETES AND METABOLIC SYNDROME
Novel insulin, insulin-fusion proteins and insulin homologs protein-small molecule drug conjugates, where conjugation takes place through the use of cleavable and non-cleavable linkers are disclosed. The small molecules chemically linked to the protein carrier are imported into the specific insulin-responsive target tissue or cell through receptor-mediated endocytosis and released from the carrier protein through enzymatic cleavage of the linker-drug moiety or through lysosomal degradation of the carrier protein. Free drug can then act to modify insulin receptor-triggered biochemical pathways that are altered in conditions of insulin-resistance. Drug will correct altered pathway allowing re-sensitization of receptor signaling. This will greatly aid in the resolution of pathologies either initiated at the onset of insulin resistance or exacerbated by it.
1 . A compound having a structure of Formula (I):
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof: wherein:
m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
X1 is a biologically active polypeptide or hormone;
X2 is a linker; and
X3 is a therapeutic compound.
2 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X1 is selected from the group consisting of insulin, insulin-like proteins and homologs comprising an amino acid sequence set forth in the table below.
SEQ ID & Name
Amino Acid Sequence
Glargine
>A chain: GIVEQCCTSICSLYQLENYCG
>B chain: FVNQHLCGSHLVEALYLVCGERGFFYTPKTRR
Degludec
>A Chain: FVNQHLCGSHLVEALYLVCGERGFFYTPK
>B Chain: GIVEQCCTSICSLYQLENYCN
Aspart
>A chain: GIVEQCCTSICSLYQLENYCN
>B chain: FVNQHLCGSHLVEALYLVCGERGFFYTDKT
Lispro
>A chain: GIVEQCCTSICSLYQLENYCN
>B chain: FVNQHLCGSHLVEALYLVCGERGFFYTKPT
Detemir
>A chain: GIVEQCCTSICSLYQLENYCN
>B chain: FVNQHLCGSHLVEALYLVCGERGFFYTPK
Glulisine
>A chain: GIVEQCCTSICSLYQLENYCN
>B chain: FVKQHLCGSHLVEALYLVCGERGFFYTPET
WT Human Insulin
>A Chain: GIVEQCCTSICSLYQLENYCN
>B Chain: FVNQHLCGSHLVEALYLVCGERGFFYTPKT
Human Thioredoxin
MVKQIESKTAFQEALDAAGDKLVVVDFSATWSGPCKMIKPFFHSLSEKYSNVIFLEVDVDDCQD
C32S
VASECEVKCMPTFQFFKKGQKVGEFSGANKEKLEATINELV
Human Thioredoxin
MVKQIESKTAFQEALDAAGDKLVVVDFSATWCGPSKMIKPFFHSLSEKYSNVIFLEVDVDDCQD
C35S
VASECEVKCMPTFQFFKKGQKVGEFSGANKEKLEATINELV
Human Thioredoxin
MVKQIESKTAFQEALDAAGDKLVVVDFSATWSGPSKMIKPFFHSLSEKYSNVIFLEVDVDDCQD
C32S C35S
VASECEVKCMPTFQFFKKGQKVGEFSGANKEKLEATINELV
Human Thioredoxin
MVKQIESKTAFQEALDAAGDKLVVVDFSATWCGPCKMIKPFFHSLSEKYSNVIFLEVDVDDCQD
WT
VASECEVKCMPTFQFFKKGQKVGEFSGANKEKLEATINELV
General Format of mature Insulin = B chain-A Chain
General format of insulin-Thioredoxin fusion proteins = Thioredoxin (WT, C32S, C35S, C32S C35S)-B chain insulin-A chain insulin or B chain insulin-A chain insulin- Thioredoxin (WT, C32S, C35S, C32S C35S).
3 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof: of claim 1 , wherein m is 1, 2, 3, 4, 5, 6, 7, or 8 and wherein n is 2, 3, 4, 5, 6, 7, 8, or 9.
4 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X2 is selected from the group consisting of:
Linker
Structure
K-1 Cleavable Linker
K-2 Cleavable Linker
K-3 Cleavable Linker
K-4 Cleavable Linker
K-5 Cleavable Linker
K-6 Cleavable Linker
K-7 Cleavable Linker
K-8 Cleavable Linker
K-9 Cleavable Linker
K-10 Cleavable Linker
K-11 Cleavable Linker
K-12 Cleavable Linker
K-13 Cleavable Linker
K-14 Cleavable Linker
K-15 Cleavable Linker
K-16 Cleavable Linker
K-17 Cleavable Linker
K-18 Cleavable Linker
K-19 Non- Cleavable Linker
K-20 Non- Cleavable Linker
K-21 Non- Cleavable Linker
K-22 Non- Cleavable Linker
K-23 Non- Cleavable Linker
K-24 Non- Cleavable Linker
5 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X2 is bound to X1 at a Cys residue or a Lys residue thereof.
6 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X3 is an agent to treat insulin resistance, type 2 diabetes and metabolic syndrome.
7 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X3, is selected from the group consisting of JNK (c-Jun N-terminal kinase) inhibitors, PKR-like endoplasmic reticulum kinase (PERK) inhibitors, PERK (PKR-like endoplasmic reticulum kinase), PTP1B (protein-tyrosine phosphatase 1B), AKT (Protein Kinase B) an antidiabetic, a neddylation inhibitor, a ubiquitin-activating enzyme inhibitor, a ubiquitin-activating enzyme E1 inhibitor, and a proteasome inhibitor.
8 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof of claim 1 , wherein X3 is selected from the group consisting of:
Compound Name
Structure
((1R,2R,4S)-4-(4-(((R)-2,3-dihydro- 1H-inden-1-yl)amino)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)-2- hydroxycyclopentyl)methyl sulfamate
4-Amino-7-[(1R,4R,5S)-4,5- dihydroxy-3- [sulfamoylamino )methyl]cyclopent- 2-en-1-yl]-5-[2-(2-ethoxy-6-fluoro- phenyl)ethynyl]pyrrolo[2,3-d]pyrimidine
((2S,3R,4S,5S)-5-(6-((3- ethynylphenyl)amino)-9H-purin-9- yl)-3,4-dihydroxytetrahydrofuran-2- yl)methyl sulfamate
((1R,2R,3S,4R)-2,3-dihydroxy-4- ((2-(3- (trifluoromethyl)phenyl)pyrazolo [1,5-a]pyrimidin-7- yl)amino)cyclopentyl)methyl sulfamate
1-(5-(4-amino-7-methyl-7H- pyrrolo[2,3-d]pyrimidin-5-yl)indolin- 1-yl)-2-(3- (trifluoromethyl)phenyl)ethan-1- one
4-(2-amino-4-methyl-3-(2- methylquinolin-6-yl)benzoyl)-1- methyl-2,5-diphenyl-1,2-dihydro- 3H-pyrazol-3-one hydrochloride
(E)-N-(4-(1-benzoylpiperidin-4- yl)butyl)-3-(pyridin-3-yl)acrylamide hydrochloride
2-[6-(4-chlorophenoxy)hexyl]-1- cyano-3-pyridin-4-ylguanidine
4-(5-methyl-4-(tosylmethyl)oxazol- 2-yl)-N-(pyridin-3- ylmethyl)benzamide
N-([1,1′-bipheny]-2-yl)-8-(4- (pyridin-3-yl)-1H-1,2,3-triazol-1- yl)octanamide
N-(4-((3.5- difluorophenyl)sulfonyl)benzyl) imidazo[1,2-a]pyridine-6- carboxamide
4-(((7-bromo-2-methyl-4-oxo-3,4- dihydroquinazolin-6- yl)methyl)(prop-2-yn-1-yl)amino)-N- (pyridin-3-ylmethyl)benzamide
2-(carboxyformamido)-4,5,6,7- tetrahydrothieno[2,3-c]pyridine-3- carboxylic acid
2-((2- (tetradecyloxy)phenyl)carbamoyl) benzoic acid
methyl 5-((N-(4-(N-(2-methoxy-2- oxoethyl)methylsulfonamido) benzyl)-1-phenylmethyl)sulfonamido)- 2- ((4-methylbenzyl)oxy)benzoate
((3-bromo-7-cyanonaphthalen-2- yl)difluoromethyl)phosphonic acid
4-hydroxy-3,3-dimethyl-2H- benzo[g]indole-2,5(3H)-dione
ethyl 2-amino-6-chloro-4-(1-cyano- 2-ethoxy-2-oxoethyl)-4H- chromene-3-carboxylate
dibenzo[cd,g]indazol-6(2H)-one
3-(3-(2-(piperidin-1- yl)ethoxy)phenyl)-5-(1H-1,2,4- triazol-5-yl)-1H-indazole hydrochloride
N-(4-amino-5-cyano-6- ethoxypyridin-2-yl)-2-(2,5- dimethoxyphenyl)acetamide
N-(3-cyano-4,5,6,7- tetrahydrobenzo[b]thiophen-2-yl)- 1-naphthamide
(E)-3-(4-(dimethylamino)but-2- enamido)-N-(4-((4-(pyridin-3- yl)pyrimidin-2- yl)amino)phenyl)benzamide
(E)-3-(4-(dimethylamino)but-2- enamido)-N-(2-methyl-4-((4- (pyridin-3-yl)pyrimidin-2- yl)amino)phenyl)benzamide
(E)-3-(4-(dimethylamino)but-2- enamido)-N-(4-((4-(2- phenylpyrazolo[1,5-a]pyridin-3- yl)pyrimidin-2- yl)amino)phenyl)benzamide
sodium (1E.3R,4R,6R,7Z,9Z, 11E)- 3,6,13-trihydroxy-3-methyl-1-(R)- 6-oxo-3,6-dihydro-2H-pyran-2- yl)trideca-1,7,9,11-tetraen-4-yl hydrogen phosphate
3-(4-methylpiperazine-1-carbonyl)- 7-oxabicyclo[2.2.1]heptane-2- carboxylic acid
(E)-3-(4-(dimethylamino)but-2- enamido)-N-(4-((4-(2- phenylpyrazolo[1,5-a]pyridin-3- yl)pyrimidin-2- yl)amino)phenyl)benzamide
(2R)-2-hydroxy-3-((2S,3S,6R)-3- hydroxy-8-((2R,E)-4- ((2R,5R,6′S,8′R)-8′-hydroxy-6′- ((1S,3S)-1-hydroxy-3-((2S,3R,6S)- 3-methyl-1,7- dioxaspiro[5.5]undecan-2-yl)butyl) 7′-methyleneoctahydro-3H,3′H- spiro[furan-2,2′-pyrano[3,2-b] pyran]-5-yl)but-3-en-2-yl)-10- methyl-1,7-dioxaspiro[5.5]undec- 10-en-2-yl)-2-methylpropanoic acid
9 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:
Compound
Structure
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10
B11
B12
B13
B14
B15
B16
B17
B18
B19
B20
B21
B22
B23
B24
B25
B26
B27
B28
B29
B30
B31
B32
B33
B34
B35
B36
B37
B38
B39
B40
B41
B42
B43
B44
B45
B46
B47
B48
B49
B50
B51
B52
B53
B54
B55
B56
B57
B58
B59
B60
B61
B62
B63
B64
B65
B66
B67
B68
B69
B70
B71
B72
B73
B74
B75
B76
B77
B78
B79
B80
B81
B82
B83
B84
B85
B86
B87
B88
B89
B90
B91
B92
B93
B94
B95
B96
B97
B98
B99
B100
B101
B102
B103
B104
B105
B106
B107
B108
10 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of B-37 through 54 and B-91 through B108.
11 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X2 is bound to X1 at two different sites on X1.
12 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X2 is bound to X1 at two different Cys residues on X1.
13 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X2 is bound to X1 at two different Lys residues on X1.
14 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X3 is Pevonedistat.
15 . A compound according to claim 1 , wherein X1 is an insulin polypeptide or a bioactive homolog thereof comprising a thioredoxin domain, X2 is a cleavable linker selected from the group consisting of glucuronide and dipeptide linkers, and X3 comprises a neddylation inhibitor and a JNK inhibitor conjugated at distinct cysteine residues.
16 . The compound of claim 15 , wherein the conjugation occurs at two cysteine residues within the thioredoxin domain of the insulin polypeptide and maintains the structural integrity of the insulin fusion protein.
17 . A pharmaceutical composition comprising the compound of claim 15 and a pharmaceutically acceptable carrier, wherein the composition is formulated for subcutaneous or intraperitoneal administration and maintains linker stability at physiological pH.
18 . A method of treating insulin resistance, obesity, diabetes mellitus, or metabolic syndrome in a subject in need thereof, comprising administering a therapeutically effective amount of the compound of claim 15 .
19 . The method of claim 18 , wherein the compound is administered once daily at a dose of 0.3 IU/kg and results in improved glucose tolerance as measured by intraperitoneal glucose tolerance test (ipGTT) at 60 minutes post-injection.
20 . The compound of claim 15 , wherein X3 is selected from the group consisting of TAS4464, MLN4924, GSK2606414, SP600125, and JD-5037.