KPT-350, an oral SINE™ compound, is being developed for the treatment of neurological, inflammatory and autoimmune indications.
Nuclear factor kappa-light-chain-enhancer of activated B cells, or NF-κB, is a protein that plays very important roles in many types of inflammation. In cells, NF-κB can be inhibited by another protein called IκB, or Inhibitor of NF-κB, that binds to NF-κB and prevents NF- κB from binding to DNA and driving inflammation. When inflammation occurs, XPO1 transports IκB out of the nucleus into the cytoplasm where it cannot inhibit NF-κB activity. When KPT-350 inhibits XPO1, IκB export to the cytoplasm is blocked and IκB accumulates in the nucleus. The IκB in the nucleus binds to NF-κB and blocks its inflammatory activity. KPT-350 also increases the concentration of other inhibitors of NF-κB in the nucleus such as FOXO and COMMD1 proteins. Thus, XPO1 inhibition leads to potent, multifaceted inhibition of the inflammatory mediator NF-κB.
KPT-350 has additional important anti-inflammatory activities such as activation of the proteins RXR  PPAR  and NRF2 (an anti-oxidant and neuroprotective protein).
KPT-350 is an IND-ready oral SINE™ compound with a preclinical data package supporting potential efficacy across a number of neurological, autoimmune and inflammatory conditions. XPO1 mediates the nuclear export of multiple proteins that impact neurological, autoimmune and inflammatory processes. Consequently, inhibition of XPO1 by KPT-350 results in a reduction in autoimmunity and inflammation and an increase in anti-inflammatory and neuroprotective responses. KPT-350 penetrates the blood brain barrier, or BBB, to a greater degree than other SINE™ compounds. Preclinical data generated largely by external collaborators show efficacy of orally-administered KPT-350 and related SINE™ compounds in animal models of amyotrophic lateral sclerosis, or ALS; traumatic brain injury, or TBI; multiple sclerosis, or MS; Duchenne Muscular Dystrophy, or DMD; systemic lupus erythematosus, or lupus; and rheumatoid arthritis, or RA.