Compounds, compositions, methods, and uses for treating insulin resistance, type 2 diabetes and metabolic syndrome
View Patent ↗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):
X1-[X2-(X3) m]n (I)
or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof: wherein:
m is 1, 2, or 3;
n is 1, 2, or 3;
X1 is a wild type human insulin;
X2 is a glucuronide or dipeptide cleavable linker; and
X3 is Pevonedistat.
2. The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, or tautomer thereof: of claim 1 , wherein n is 2 or 3.
3. The compound, or a pharmaceutically acceptable salt, solvate, hydrate, isomer, and 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 and
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 or a Lys residue thereof.
5. 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:
6. 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 and B-49.
7. 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.
8. 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.
9. 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.