AUGMENTATION OF HEMATOPOIETIC STEM CELL PROLIFERATION TO INCREASE THE EFFICIENCY OF STEM CELL TRANSPLANTATION

Abstract

Hematopoietic Stem Cells (HSC) have capability to self renew and give rise to all blood cell types. Hematopoiesis is a process of generation of all blood cells(red, white and platelets)in bone marrow. These blood cells develop from HSC’s released into blood stream along with small number of stem cells. Nowadays bone marrow transplantation (BMT) or hematopoietic stem cell transplantation is an effective way to treat cancer because chemotherapy and radiation, are toxic to the bone marrow. Therefore, it is necessary to increase the number of HSC’s in blood prior reaching the bone marrow. The objective of the work is to increase the proliferation of HSC’s needed during transplantation. HSC’s have two main characteristics of proliferation and differentiation which is regulated by c-Kit, a protein tyrosine kinase family receptor. Binding of Stem Cell Factor to c-KIT results in receptor dimerization and activates c-KIT activity. In contrary Src homology region2 (SH-2) domain-containing phosphatase-1 (SHP-1) binds to phosphotyrosine residue 570 of c-KIT and negatively regulates proliferation of HSC’s. In order to increase proliferation we have designed inhibitors against SHP-1to inactivate enzyme activity. Till date only NSC87877 was reported to inhibit SHP-1/2,but we have found some more inhibitors which have higher binding energy with SHP-1 than NSC87877.On the basis of our screening results we have developed a pharmacophore and QSAR model and generated analog ligands. Out of which ligands which followed Lipinski rule of 5and binding energy better than NSC87877 with SHP-1 were further tested using 3D-QSAR model development.