Combined chemical modification of sphingosine-1-phosphate (s1p) and cxcr4 signalling pathways for hematopoietic stem cell (hsc) mobilization and engraftment

A method comprising administering to a subject in need of hematopoietic stem cell (HSC) engraftment a CXCR4 antagonist and an agent selected from the group consisting of:

• a) (R)-3-Amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid (W146), wherein the ratio of the concentration of the CXCR4 antagonist to the concentration of the W146 compound is (0.5-0.6):1.0;
• b) 3-[[2-[4-phenyl-3-(trifluoromethyl)phenyl]-1-benzothiophen-5-yl]methylamino]propanoic acid (AUY954), wherein the ratio of the concentration of the CXCR4 antagonist to the concentration of the AUY954 compound is (0.4-2.5):1.0;
• c) 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), wherein the ratio of the concentration of the CXCR4 antagonist to the concentration of the 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol compound is (0.4-3.0):1.0;
• and
• d) 5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (SEW2871), wherein the ratio of the concentration of the CXCR4 antagonist to the concentration of the 5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole compound is (0.25-1.0):1.0.

A method comprising administering to a subject in need of hematopoietic stem cell (HSC) mobilization a CXCR4 antagonist and an agent selected from the group consisting of:

• a) (R)-3-Amino-4-(3-hexylphenylamino)-4-oxobutylphosphonic acid (W146), wherein the ratio of the concentration of the CXCR4 antagonist to the concentration of the W146 compound is (1.25-2.0):1;
• b) 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), wherein the ratio of the concentration of the CXCR4 antagonist to the concentration of the 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol compound is 5:1;
• and
• c) 5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole (SEW2871), wherein the ratio of the concentration of the CXCR4 antagonist to the concentration of the 5-[4-phenyl-5-(trifluoromethyl)-2-thienyl]-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole compound is (1.25-5.0):1.0.

A pharmaceutical composition or kit comprising at least one CXCR4 antagonist and an agent selected from the group consisting of:

• a) W146 in an effective amount to promote HSC engraftment or migration in a subject;
• b) AUY in an effective amount to promote HSC engraftment in a subject;
• c) FTY720 in an effective amount to promote HSC engraftment or migration in a subject;
• and
• d) SEW2781 in an effective amount to promote HSC engraftment or migration in a subject.