Delanzomib

Delanzomib is an orally bioavailable inhibitor of chymotrypsin-like proteasome activity (IC₅₀ = 3.8 nM in isolated human erythrocytes) that only marginally inhibits tryptic and peptidyl glutamyl proteasome activity.¹ Delanzomib pre-treatment (20 nM) in vitro inhibits IκBα degradation, NF-κB activation, and the expression of NF-κB-regulated genes, including IκBα, XIAP, TNF-α, IL-1β, ICAM-1, and VEGF. Delanzomib induces apoptosis in multiple myeloma cell lines and inhibits proliferation in a panel of human hematologic and solid tumor cell lines (IC₅₀s = 5.6-34.2 nM). It reduces tumor weight in an RPMI 8226 human multiple myeloma mouse xenograft model when administered intravenously at doses ranging from 1.5-4 mg/kg twice daily and leads to complete tumor regression at a chronic oral dose of 13 mg/kg. Delanzomib reduces the serum level of circulating cytokines, prevents renal tissue damage, and increases lifespan in a mouse model of fatal lupus nephritis. ²

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1. Piva, R., Ruggeri, B., Williams, M., et al. CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood 111(5), 2765-2775 (2008).

2. Seavey, M.M., Lu, L.D., Stump, K.L., et al. Novel, orally active, proteasome inhibitor, delanzomib (CEP-18770), ameliorates disease symptoms and glomerulonephritis in two preclinical mouse models of SLE. Int. Immunopharmacol. 12(1), 257-270 (2012).