Compositions and methods of using tyrosine kinase inhibitors

Abstract

The present invention provides compositions and methods of inhibiting tyrosine phosphorylation. In one aspect, a composition comprising a low-dosage tyrosine kinase inhibitor, where the low-dosage tyrosine kinase inhibitor decreases tyrosine phosphorylation, is provided. In another aspect, a method for treating cardiovascular disease or condition associated with a RASopathy having aberrant protein tyrosine phosphorylation is described. Methods for treating congenital heart disease associated with Noonan or Noonan syndrome with multiple lentigines and decreasing aberrant levels of Protein Zero-Related (PZR) tyrosyl phosphorylation are also described.

What is claimed is: 
     
         1 . A method of treating a cardiovascular disease or condition having aberrant protein tyrosine phosphorylation in a subject, comprising administering a low-dosage of a tyrosine kinase inhibitor to a subject in need thereof, wherein the tyrosine kinase inhibitor decreases aberrant levels of tyrosine phosphorylation and improves at least one cardiac function in the subject,
 wherein the low-dosage is in the range of about 175 fold to about 250 fold lower than a chemotherapeutic dosage of the tyrosine kinase inhibitor.   
     
     
         2 . A method of treating congenital heart disease comprising administering a low-dosage of a tyrosine kinase inhibitor to a subject in need thereof, wherein the tyrosine kinase inhibitor decreases aberrant levels of tyrosine phosphorylation and improves at least one cardiac function in the subject,
 wherein the low-dosage is in the range of about 175 fold to about 250 fold lower than a chemotherapeutic dosage of the tyrosine kinase inhibitor.   
     
     
         3 . A method of treating a cardiovascular disease or condition associated with a RASopathy having aberrant protein tyrosine phosphorylation comprising administering a low-dosage of a tyrosine kinase inhibitor to a subject in need thereof, wherein the tyrosine kinase inhibitor decreases aberrant levels of tyrosine phosphorylation and improves at least one cardiac function in the subject,
 wherein the low-dosage is in the range of about 175 fold to about 250 fold lower than a chemotherapeutic dosage of the tyrosine kinase inhibitor.   
     
     
         4 . The method of  claim 2 , wherein the congenital heart disease is associated with RASopathy. 
     
     
         5 . The method of  claim 3 , wherein the cardiovascular disease or condition is congenital heart disease. 
     
     
         6 . The method of  claim 4 , wherein the RASopathy is selected from the group consisting of Neurofibromatosis Type 1, Noonan syndrome, Noonan syndrome with multiple lentigines (Leopard syndrome), capillary malformation-arteriovenous malformation syndrome, Costello syndrome, cardio-facio-cutaneous syndrome, and Legius syndrome. 
     
     
         7 . The method of  claim 1 , wherein the cardiac function is selected from the group consisting of myofibrilar organization, cardiomyocyte contractility, SERCA2A expression, and cardiac fibrosis. 
     
     
         8 . The method of any one of  claim 1 , wherein the subject is a pediatric patient. 
     
     
         9 . The method of  claim 8 , wherein the pediatric subject is less than 12 years of age. 
     
     
         10 . The method of  claim 1 , wherein the subject is greater than 18 years of age. 
     
     
         11 . The method of  claim 1 , wherein the aberrant levels of tyrosine phosphorylation comprise aberrant levels of tyrosine phosphorylated Protein Zero-Related (PZR). 
     
     
         12 . The method of  claim 11 , wherein the low-dosage tyrosine kinase inhibitor decreases PZR tyrosine phosphorylation. 
     
     
         13 . The method of  claim 1 , wherein the low-dosage tyrosine kinase inhibitor provides an anti-fibrotic effect in cardiac tissue to the subject. 
     
     
         14 . The method of  claim 1 , wherein the tyrosine kinase inhibitor is selected from the group consisting of afatinib, axitinib, bosutinib, cabozantinib, cediranib, ceritinib, crizotinib, dabrafenib, dasatinib, erlotinib, everolimus, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, lestaurtinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, regorafenib, ruxolitinib, semananib, sirolimus, sorafenib, sunitinib, temsirolimus, tofacitinib, trametinib, vandetanib, vemurafenib, A419259, AP23451, AP23464, AP23485, AP23588, AZD0424, AZM475271, BMS354825, CGP77675, CU201, E MD 2076, KB SRC 4, KX2361, KX2-391, MLR 1023, MNS, PCI-32765, PD166285, PD180970, PKC-412, PKI166, PP1, PP2, SRN 004, SU6656, TC-S7003, TG100435, TG100948, TX-1123, VAL 201, WH-4-023, XL 228, altenusin, bosutinib, damnacanthal, dasatinib, herbimycin A, indirubin, neratinib, lavendustin A, pelitinib, piceatannol, saracatinib, Srcl1, and analogs thereof.