CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib

Abstract

Modulating protein ubiquitination via proteasome inhibition represents a promising target for cancer therapy, because of the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-kappaB (NF-kappaB) activity and the expression of several NF-kappaB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong antiangiogenic activity and potently represses RANKL-induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition.

The novel 2-selective proteasome inhibitor LU-102 synergizes with bortezomib and carfilzomib to overcome proteasome inhibitor resistance of myeloma cells

“…The two approved proteasome-inhibiting drugs, bortezomib and carfilzomib, by design target the β5 subunit of the constitutive proteasome and the immunoproteasome, which mediate the rate-limiting proteolytic proteasome activity. 1,12 Several β5-targeted next generation proteasome inhibiting drugs like delanzomib 13 (CEP-18770), ixazomib 14 (MLN-2238), and oprozomib 15 (ONX-0912) are under development. Mutations in the bortezomib binding pocket 16,17 have been suggested to provide bortezomib resistance in myeloma, based on in vitro studies, but have not been confirmed in vivo.…”

Future Cancer Therapy with Molecularly Targeted Therapeutics: Challenges and Strategies

“…CEP18770 (Cephalon Inc.): As a reversible boronic acid proteasome inhibitor, CEP18770 caused similar proteasome and apoptotic profi les in multiple myeloma xenograft models following intravenous or oral administration (Piva, 2008;Marblestone, 2009). CEP-18770 also induces synergistic inhibition of multiple myeloma cell viability with combination with melphalan or bortezomib.…”

Ready for a comeback of natural products in oncology

“…Proteasome inhibitors have also been identified from plant extracts. This is the case for celastrol from the Chinese medicinal orally-active inhibitor of the chymotrypsin-like activity [64,65]. These proteasome inhibitors are primarily designed as anticancer agents but they can be of interest for other pathologies characterized by alterations in the proteasome proteolytic pathway including autoimmune and inflammatory diseases, myocardial infarction, and ischemic brain injury [66].…”