RK-24466

RK-24466 (KIN 001-51) is a potent and selective Lck inhibitor; inhibits Lck (64-509) and LckCD isoforms with IC₅₀s of less than 1 and 2 nM, respectively. IC50 & Target: IC50: <1 nM (Lck (64-509)), 2 nM (LckCD)^[1] In Vitro: RK-24466 is selective for Lck over a range of receptor, non-receptor tyrosine kinases and seronine/threonine kinases. RK-24466 are potent inhibitors of IL2 production in Jurkat cells stimulated with anti-CD3 antibody, being at least 100-fold more potent than PP1. RK-24466 displays remarkable cellular selectivity^[1]. RK-24466 significantly inhibits both VSMC proliferation and migration. RK-24466 suppresses VSMC proliferation and migration via down-regulating the protein kinase B (Akt) and extracellular signal regulated kinase (ERK) pathways, and it significantly decreases the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 and, the phosphorylation of retinoblastoma protein (pRb)^[2]. In Vivo: RK-24466 inhibits T-cell receptor stimulated (a-CD3 mAb) IL-2 production in mice at low doses (ED₅₀=4 mg/kg) after ip administration. However, efficacy is greatly reduced after oral administration (ED₅₀=25 mg/kg) which is presumed to reflect poor intestinal absorption in the latter regimen. Inhibition of antigen specific T-cell immune responses is also seen for RK-24466. After administration of RK-24466 twice daily (100 mg/kg po) for 3 days during the in vivo priming phase, a 70% inhibition of IFNγ production is seen upon subsequent antigen-specific (KLH) challenge of lymphocytes from the draining lymph nodes in vitro^[3]. RK-24466 suppresses the migration of VSMCs from endothelium-removed aortic rings, as well as neointima formation following rat carotid balloon injury^[2].