Sumitomo -Â Model DSP-0390 - Emopamil-Binding Protein (EBP) Inhibitor
DSP-0390 is an emopamil-binding protein (EBP) inhibitor. EBP is an endoplasmic reticulum membrane protein involved in cholesterol biosynthesis.47 When functional, EBP mediates de novo cholesterol synthesis for cell membrane structure and signaling, enabling aberrant growth of tumors.47-50 Inhibition of EBP causes an accumulation of its substrates zymostenol and zymosterol, which contributes to lethal autophagy in several types of cancer and efficient cellular cholesterol depletion via secondary LXR activation.47-50 The gene signature associated with cholesterol biosynthesis has been correlated with certain cancer cell proliferation and an aggressive phenotype.51
Understanding our target
Cholesterol is a molecule essential for cell proliferation and cell survival.52 Some cancer cells may survive by maintaining high levels of intracellular cholesterol, either through endogenous production, reducing cholesterol breakdown, or by increasing uptake.52 EBP is involved in the final steps of cholesterol biosynthesis, autophagy, and oligodendrocyte formation.47 High expression of EBP and upregulation of the cholesterol metabolism pathway have been observed in several solid tumors.53 In patients with glioblastoma multiforme (GBM), increased de novo cholesterol synthesis is correlated with poor survival.54
Preclinical evidence
DSP-0390 has shown cytotoxic activity against GBM, colorectal cancer, and triple-negative breast cancer in vitro.
Clinical development
DSP-0390 is currently being investigated in a phase I study in patients with recurrent, high-grade glioma.
