Figure 1.
SLU-2609 is a potent inhibitor of VLA4 in vitro and mobilizes CFUs to peripheral blood in mice. (A) Structures of various canonical and novel VLA4 inhibitors. (B) BALB/c mice were injected subcutaneously (SC) with every combination of tGro-β (2.5 mg/kg), CXCR4 inhibitor plerixafor (5 mg/kg), and/or VLA4 inhibitor CWHM-823 (3 mg/kg). tGro-β was always administered as a separate SC injection. Mice treated with the triple combination of a VLA-4 inhibitor, plerixafor and tGro-β were first injected SC with a mixture of the VLA-4 inhibitor plus plerixafor followed immediately thereafter by a SC injection of tGro-β. Peripheral blood samples were collected 30, 120, and 240 minutes after injection. Samples were cultured for 6 to 8 days in mouse methylcellulose complete media and CFUs were quantified. Data are mean ± SD of 2 independent experiments; n = 8 to 10 mice per cohort. (C) G2 acute lymphoblastic leukemia cells expressing VLA-4 were preincubated with the VLA4 inhibitors shown in panel A for 15 minutes at RT. Recombinant soluble VCAM-1/Fc chimera protein was added, and mixtures were cultured for an additional 30 minutes at RT. Binding of VCAM-1 was detected by flow cytometry using a phycoerythrin-conjugated donkey anti-human Fc antibody and compared with a phycoerythrin-conjugated donkey IgG isotype control. Data are mean ± SEM of 3 independent experiments, in which samples were analyzed in duplicate in each experiment. (D) DBA/2J mice were left untreated or injected with 3 mg/kg of the indicated VLA4 inhibitors and peripheral blood samples were collected 30, 120, and 240 minutes after injection. Samples were cultured for 6 to 8 days in mouse methylcellulose complete media, and CFUs were quantified. Data are mean ± SD of 3 independent experiments; n = 15 mice per cohort. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001. IgG, immunoglobulin G; RT, room temperature; SD, standard deviation; SEM, standard error of the mean.

SLU-2609 is a potent inhibitor of VLA4 in vitro and mobilizes CFUs to peripheral blood in mice. (A) Structures of various canonical and novel VLA4 inhibitors. (B) BALB/c mice were injected subcutaneously (SC) with every combination of tGro-β (2.5 mg/kg), CXCR4 inhibitor plerixafor (5 mg/kg), and/or VLA4 inhibitor CWHM-823 (3 mg/kg). tGro-β was always administered as a separate SC injection. Mice treated with the triple combination of a VLA-4 inhibitor, plerixafor and tGro-β were first injected SC with a mixture of the VLA-4 inhibitor plus plerixafor followed immediately thereafter by a SC injection of tGro-β. Peripheral blood samples were collected 30, 120, and 240 minutes after injection. Samples were cultured for 6 to 8 days in mouse methylcellulose complete media and CFUs were quantified. Data are mean ± SD of 2 independent experiments; n = 8 to 10 mice per cohort. (C) G2 acute lymphoblastic leukemia cells expressing VLA-4 were preincubated with the VLA4 inhibitors shown in panel A for 15 minutes at RT. Recombinant soluble VCAM-1/Fc chimera protein was added, and mixtures were cultured for an additional 30 minutes at RT. Binding of VCAM-1 was detected by flow cytometry using a phycoerythrin-conjugated donkey anti-human Fc antibody and compared with a phycoerythrin-conjugated donkey IgG isotype control. Data are mean ± SEM of 3 independent experiments, in which samples were analyzed in duplicate in each experiment. (D) DBA/2J mice were left untreated or injected with 3 mg/kg of the indicated VLA4 inhibitors and peripheral blood samples were collected 30, 120, and 240 minutes after injection. Samples were cultured for 6 to 8 days in mouse methylcellulose complete media, and CFUs were quantified. Data are mean ± SD of 3 independent experiments; n = 15 mice per cohort. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001; ∗∗∗∗P < .0001. IgG, immunoglobulin G; RT, room temperature; SD, standard deviation; SEM, standard error of the mean.

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