Integrin α4β1 is an integrin dimer and is composed of CD49d (alpha 4) and CD29 (beta 1). Specifically, integrin α4β1 promotes the inflammatory response of the immune system by helping white blood cells move to tissues that need inflammation. Besides, it is a key factor in cell adhesion. However, it is not until leukocytes are activated by chemotactic agents or other stimulants that VLA-4 adheres to its appropriate ligand. The main ligands of VLA-4 include VCAM-1 and fibronectin. Moreover, adhesion molecules make leukocytes adhere and roll along the surface of endothelial cells, and control the migration of leukocytes into inflammatory tissues. Furthermore, VLA4 is the only VLA in cell-cell and cell-matrix adhesion. VCAM-1 is a potential marker of disease activity under inflammatory conditions, including SLE nephritis and atherosclerosis. Firategrast (SB 683699) is an orally active and specific α4β1/α4β7 integrin antagonist.
Firategrast is an orally active and specific α4β1/α4β7 integrin antagonist.
But, how does Firategrast work on the α4β1/α4β7 integrin? Let’s discuss it in detail. In the beginning, Firategrast is an orally active and specific α4β1/α4β7 integrin antagonist. Meanwhile, Firategrast reduces the trafficking of lymphocytes into the central nervous system (CNS) and decreases multiple sclerosis (MS) activity.
In the second place, Firategrast with 0.1-10 µM for 1 hour significantly reduces chronic lymphocytic leukemia (CLL) cell adhesion. Nonetheless, Firategrast is a potent Integrin α4β1 (VLA-4) antagonist. Particularly, it inhibits the binding of soluble VCAM/Fc chimeric protein (sVCAM-1) to G2 acute lymphoblastic leukemia (ALL) cells (IC50=198 nM). Obviously, VLA-4 includes CD49d (α4) and CD29 (β1).
Last but not the least, Firategrast shows an overall reduction of leukemic cells in the spleen with 30 mg/kg/day in drinking water for 19 or 14 days.
All in all, Firategrast is an orally active and specific α4β1/α4β7 integrin antagonist and decreases multiple sclerosis (MS) activity.
References:
Eva Szenes, et al. Leukemia. 2020 Sep;34(9):2498-2502.