Opaganib

Opaganib is a selective inhibitor of sphingosine kinase 2 (SPHK2; Ki = 9.8 μM), a lipid kinase that catalyzes formation of the lipid signaling molecule sphingosine 1-phosphate (S1P). S1P promotes cancer growth, and proliferation and pathological inflammation, including TNF-α signaling and other inflammatory cytokine production. By inhibiting the SK2 enzyme, opaganib blocks the synthesis of S1P which regulates fundamental biological processes such as cell proliferation, migration, immune cell trafficking and angiogenesis, and is also involved in immune-modulation and suppression of innate immune responses from T cells. Opaganip has similar potency toward sphingosine kinase (SK2) and dihydroceramide desaturase (DES1). Inhibition of SK2 activity causes downregulation of the expression of myeloid cell leukemia 1 (Mcl-1) and c-Myc and suppresses the activation of nuclear factor-kappa B (NF-kB), thereby promoting apoptosis and inhibiting proliferation and inflammation. In parallel, inhibition of DES1 promotes autophagy and promotes Rb phosphorylation resulting in suppression of proliferation. Opaganib inhibits proliferation of a variety of cancer cells, including HepG2 liver, A-498 kidney, PANC-1 pancreas and HT-29 colon cells (IC50s = 6, 12.2, 32.8, and 48.1 µM, respectively). It also has been used in vivo to reduce tumor growth in a mouse syngeneic model of mammary adenocarcinoma and to reduce colonic inflammation in mouse and rat models of Crohn’s disease. Opaganib shows anticancer, anti-inflammatory and antiviral activities. Opaganib is an investigational drug targeting several potential oncology, inflammatory and gastrointestinal indications and it is also under development as a potential therapy for COVID-19.