Targeting anabolic drugs for accelerated fracture repair

Abstract

Aspects of the disclosure include material and methods for the targeted delivery of growth factors, vasoactive peptides and other representative anabolic peptide drugs from different signaling cascades to bone fracture for accelerated healing is disclosed herein. Aspects of the disclosure can be used to treat bone fractures and bone defects.

1 - 18 . (canceled) 
     
     
         19 . A compound having a structure of:
   X-Y-Z   wherein:
 X is a Src kinase inhibitor; 
 Y is absent or a linker; and 
 Z is a bone-targeting molecule, 
   or a pharmaceutically acceptable salt thereof.   
     
     
         20 . The compound of  claim 19 , wherein Z comprises a polypeptide. 
     
     
         21 . The compound of  claim 19 , wherein Z comprises not less than 4 and not more than 40 amino acid residues. 
     
     
         22 . The compound of  claim 21 , wherein at least one amino acid is aspartic acid or glutamic acid. 
     
     
         23 . The compound of  claim 19 , wherein Z comprises not less than 6 and not more than 20 glutamic acid residues. 
     
     
         24 . The compound of  claim 23 , wherein Z is 10 D-glutamic acid residues. 
     
     
         25 . The compound of  claim 19 , wherein Z comprises not less than 6 and not more than 20 aspartic acid residues. 
     
     
         26 . The compound of  claim 25 , wherein Z is 10 D-aspartic acid residues. 
     
     
         27 . The compound of  claim 19 , wherein Y is a releasable linker or non-releasable linker. 
     
     
         28 . The compound of  claim 27 , wherein the releasable linker comprises at least one releasable linker group, each releasable linker group being independently selected from the group consisting of a disulfide (S-S), an ester, and a protease specific amide bond. 
     
     
         29 . The compound of  claim 27 , wherein the non-releasable linker comprises at least one non-releasable linker group, each non-releasable linker group being independently selected from the group consisting of a carbon-carbon bond, ether, and an amide. 
     
     
         30 . The compound of  claim 27 , wherein Y comprises one or more ethylene glycol unit. 
     
     
         31 . The compound of  claim 30 , wherein Y comprises 2-8 oxyethylene units. 
     
     
         32 . The compound of  claim 19 , wherein the Src inhibitor is selected from the group consisting of Dasatinib and E739. 
     
     
         33 . A compound having a structure of:
   X-Y-Z   wherein:
 X is an agent that activates sphingosine-1-phosphate (S1P); 
 Y is absent or a linker; and 
 Z is a bone-targeting molecule, 
   or a pharmaceutically acceptable salt thereof.   
     
     
         34 . The compound of  claim 33 , wherein the S1P is selected from the group consisting of a Sphingosine-1-phosphate receptor 1 (S1P1R) agonist and a S1P lyase inhibitor. 
     
     
         35 . The compound of  claim 34 , wherein the SIP1R agonist is Ozanimod. 
     
     
         36 . The compound of  claim 34 , wherein the S1P lyase inhibitor is 4-deoxypyridoxine (DOP). 
     
     
         37 . A compound having a structure of:
   X-Y-Z   wherein:
 X is a neuropeptide; 
 Y is absent or a linker; and 
 Z is a bone-targeting molecule, 
   or a pharmaceutically acceptable salt thereof.   
     
     
         38 . The compound of  claim 37 , wherein the neuropeptide is selected from the group consisting of Substance P, vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), amylin, and calcitronin gene-like related peptide (CGRP).