Compounds, compositions, methods, and uses for treating cancer and immunological disorders
The present disclosure provides novel polypeptide-therapeutic compound or hormone-therapeutic compound conjugates using cleavable or non-cleavable linkers, whereby the polypeptide or hormone serves to target specific cells using receptor expression on the targeted cell to bind the ligand (polypeptide or hormone) carrying the therapeutic compound unlike antibody drug conjugates. Upon binding, the ligand and the therapeutic compound (multiples of the therapeutic compound in some embodiments) enter the cell by receptor-mediated endocytosis, and release drugs conjugated to the ligand by linkers, to interact with intracellular components to enhance, restore, or block a signal transduction process. The ligands for the polypeptide-therapeutic compound or hormone-therapeutic compound conjugates include, but are not limited to: cytokines, growth factors and hormones among other proteins with corresponding cell surface specific receptors. The disorders targeted by such polypeptide-therapeutic compound or hormone-therapeutic compound conjugates include, but are not limited to: immunological disorders (e.g., allergy and autoimmune disorders) and cancer.
1 . A compound having a structure of Formula (III):
X 1 —[X 2 —(X 3 ) m ] (III),
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;
X 1 is an IL-2 polypeptide or a bio-active homolog polypeptide thereof comprising an amino acid sequence set for in SEQ ID NO:2;
X 2 comprises is at least one linker, wherein the at least one linker includes one or more linker types is conjugated to the IL-2 polypeptide or a bio-active homolog polypeptide thereof; and
X 3 is a therapeutic compound payload for treating immunological disorders, wherein X 3 is a neddylation inhibitor wherein the therapeutic compound payload is conjugated to the at least one linker.
2 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X2 is a non-cleavable linker.
3 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X2 is a cleavable linker selected from the group consisting of:
Com-
pound
Structure
K-1
K-2
K-3
K-4
K-5
K-6
K-7
K-8
K-9
K-10
K-11
K-12
K-13
K-14
K-15
K-16
K-19
and
K-20
wherein the left side of X2, as drawn, is bound to X1, and the right side of X2, as drawn, is bound to X3 and wherein R is H, alkyl, aryl, arylalkyl, a glycol ether, or a glycol linker.
4 . 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 thereof or a Lys residue thereof.
5 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X3 is an immunomodulating agent.
6 . 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: pevonedistat; TASI (((2S,3S,4R,5R)-5-(4-amino-5-((4,7-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl) ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl sulfamate); TAS2 (((1S,2R,3S,4R)-4-(4-amino-5-((4,7-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-8-yl) ethynyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroxycyclopentyl)methyl sulfamate); TAK7243 (((1R,2R,3S,4R)-2,3-dihydroxy-4-((2-(3-(trifluoromethyl)phenyl) pyrazolo[1,5-a]pyrimidin-7-yl)amino)cyclopentyl)methyl sulfamate); ABPA3 ([(2R,3S,4R,5R)-5-[6-(3-ethynylanilino) purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methyl sulfamate); and TAS4464 (7H-Pyrrolo[2,3-d]pyrimidin-4-amine, 7-[5-[(aminosulfony 1)amino]-5-deoxy-beta-D-ribofuranosyl]-5-[2-(2-ethoxy-6-fluorophenyl) ethynyl]-), wherein R 1 is alkyl, aryl, arylalkyl, arylalkyne, arylalkene, heterocyclyl, or heteroaryl and R2 is H, alkyl, or aryl.
7 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein the compound of Formula (III) is selected from the group consisting of:
Com-
pound
Structure
B-1
B-2
B-3
B-4
B-5
B-6
B-7
B-8
B-9
B-10
B-11
B-12
B-13
B-14
B-15
B-16
B-17
B-18
B-30
B-31
B-48
and
B-49
wherein R is H, alkyl, aryl, arylalkyl, a glycol ether, or a glycol linker; q is 1, 2, 3, or 4; n1 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and n2 is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
8 . A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, of claim 1 and a pharmaceutically acceptable carrier.
9 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X2 is a mixture of X 2b and X 2c , X 2b is a linker that is bound to one Cys residue on X 1 , X 2c is a linker that is bound to two different Cys residues on X 1 , wherein n is 2, 3, 4, 5, or 6, and wherein SEQ ID NO:2 has with amino acid sequence MVKQIESKTAFQEALDAAGDKL VVVDFSATWCGPCKMIKPFFHSLSEKYSNVIFLEVDVDDCQDVASECEVKCMPTFQF FKKGQKVGEFSGANKEKLEATINELVGSAMAPTSSSTKKTQLQLEHLLLDLQMILNGI NNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT.
10 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein the compound of Formula (III) is B-49.
11 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein X2 is X2b or X2c, wherein X2b is a linker that is bound to one Cys residue on X1, and n is n1, wherein n1 corresponds to the number of X2b moieties bound to X1, and wherein X2c is a linker that is bound to two different Cys residues on X1, wherein n is n2, wherein n2 corresponds to the number of X2c moieties bound to X1.
12 . The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof, of claim 1 , wherein the compound of Formula (III) is B-49.
13 . The compound of claim 1 , wherein the linker is cleavable under intracellular conditions and facilitates endocytic release of the therapeutic compound payload.