ML401

Functional Antagonists of EBI-2

PMID:25834900DOI:NBK280046

A robust antibody response is essential for efficient identification and eradication of pathogenic microbes and toxins, whereas dysregulation of the antibody response can lead to autoimmune disease. Specific antigen encounter by B lymphocytes induces clonal expansion that encompasses several distinct stages of differentiation. During this differentiation process, a critical cell fate decision is made wherein some B cells will undergo terminal differentiation into antibody-producing cells, while a separate cohort will assume a distinct pathway of differentiation to become long-lived memory B cells. An exciting new development in the field is the revelation of a novel chemotactic axis involving the recognition of oxysterol compounds by the orphan G-protein-coupled receptor (GPCR), Epstein-Barr virus-induced gene 2 (EBI2). EBI2 is expressed on B cells and is highly induced upon activation. Recent gene targeting experiments revealed that EBI2-/- B cells exhibited defective migration, resulting in strongly impaired T cell-dependent antibody responses. Most recently, two research teams made the unlikely discovery that oxysterol compounds, previously known to bind nuclear receptors, are the physiologic ligands for EBI2. In order to investigate the importance of EBI2 in immune processes and potential as a drug target, selective and potent antagonists with good in vivo pharmacokinetics need to be developed. This probe report describes a potent functional antagonist of EBI-2, ML401 (CID 73169083, SID 173333998), which is potent (IC50 ∼ 1 nM), displays activity in a chemotaxis assay (IC50 ∼ 6 nM), and has a clean profile in a Eurofins/Ricerca panel as well as excellent rodent pharmacokinetics. As such ML401 should be a valuable tool to explore the in vivo effects of EBI-2 inhibition.