BIO 5192 is a potent and selective small-molecule inhibitor of integrin α4β1 (VLA-4), with an IC50 value of 1.8nM[1]. VLA-4 is a crucial cell adhesion molecule on immune cells (e.g., lymphocytes, monocytes, eosinophils) that enables their adhesion to the vascular endothelium and migration into tissues, which is vital for immune cell trafficking, hematopoietic regulation, and immune response activation[2]. BIO 5192 is commonly used in research on mobilizing hematopoietic stem and progenitor cells (HSPCs), autoimmune diseases like multiple sclerosis, and potential hematological disorders (by preventing cell adhesion)[3,4].
In vitro, pretreatment of mouse myeloma WT 5TGM1-GFP cells with BIO 5192 (100nM) for 30min significantly inhibited the binding of the fluorescent probe LLP2A-Cy5 to cell surface VLA-4[5]. Pretreatment of human T lymphocytes with BIO 5192 (10μg/mL) for 5min markedly suppressed VLA-4-mediated adhesion of lymphocytes to TNF-α-activated human umbilical vein endothelial cells (HUVECs) and prevented the co-recruitment of VCAM-1 at endothelial cell contact sites[6].
In vivo, a single intravenous injection of BIO 5192 (1mg/kg) in mice induced only a moderate increase in the numbers of progenitor cells and hematopoietic stem cells (HSCs) in peripheral blood after 1h, demonstrating a relatively weak mobilization effect[7]. Combined treatment of mice with BIO 5192 (1mg/kg; i.v.) and Plerixafor (5mg/kg; s.c.) produced an additive effect on HSPC mobilization. The mobilization level peaked at 3h and persisted for at least 6h, with the effect being significantly superior to either drug alone[3].
References:
[1] LEONE D R, GIZA K, GILL A, et al. An assessment of the mechanistic differences between two integrin α4β1 inhibitors, the monoclonal antibody TA-2 and the small molecule BIO5192, in rat experimental autoimmune encephalomyelitis[J]. The Journal of Pharmacology and Experimental Therapeutics, 2003, 305(3): 1150-1162.
[2] OOSTENDORP R A J, DÖRMER P. VLA-4-mediated interactions between normal human hematopoietic progenitors and stromal cells[J]. Leukemia & Lymphoma, 1997, 24(5-6): 423-435.
[3] RAMIREZ P, RETTIG M P, UY G L, et al. BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells[J]. Blood, The Journal of the American Society of Hematology, 2009, 114(7): 1340-1343.
[4] THEIEN B E, VANDERLUGT C L, NICKERSON-NUTTER C, et al. Differential effects of treatment with a small-molecule VLA-4 antagonist before and after onset of relapsing EAE[J]. Blood, 2003, 102(13): 4464-4471.
[5] HATHI D, CHANSWANGPHUWANA C, CHO N, et al. Ablation of VLA4 in multiple myeloma cells redirects tumor spread and prolongs survival[J]. Scientific Reports, 2022, 12(1): 30.
[6] BARREIRO O, ZAMAI M, YANEZ-MO M, et al. Endothelial adhesion receptors are recruited to adherent leukocytes by inclusion in preformed tetraspanin nanoplatforms[J]. The Journal of Cell Biology, 2008, 183(3): 527-542.
[7] CAO B, ZHANG Z, GRASSINGER J, et al. Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist[J]. Nature Communications, 2016, 7(1): 11007.
BIO 5192是一种具有强效选择性的小分子整合素α4β1（VLA-4）抑制剂，IC50值为1.8nM[1]。VLA-4是免疫细胞（淋巴细胞、单核细胞、嗜酸性粒细胞等）上的关键细胞粘附分子，可帮助它们粘附在血管壁（内皮）并进入组织，对免疫细胞运输、造血调控和免疫反应激活至关重要[2]。BIO 5192通常用于动员造血干细胞和祖细胞（HSPCs）、多发性硬化症等自身免疫疾病及潜在血液疾病（通过防止细胞粘连）的研究[3,4]。
在体外，BIO 5192（100nM）预处理小鼠骨髓瘤WT 5TGM1-GFP细胞30min，显著抑制了荧光探针LLP2A-Cy5与细胞表面VLA-4的结合[5]。BIO 5192（10μg/mL）预处理人类T淋巴细胞5min，显著抑制了VLA-4介导的淋巴细胞与TNF-α活化的人脐静脉内皮细胞（HUVECs）之间的粘附，并阻止了VCAM-1在内皮细胞接触部位的共募集[6]。
在体内，BIO 5192（1mg/kg）单次静脉注射处理小鼠，1h后仅中度增加外周血中的祖细胞和造血干细胞（HSC）数量，动员效果较弱[7]。BIO 5192（1mg/kg; i.v.）与Plerixafor（5mg/kg; s.c.）联合处理小鼠，对HSPCs的动员产生叠加效应，动员水平在3h达到峰值并持续至少6h，效果显著优于单药[3]。