A novel proteasome inhibitor NPI-0052 as an anticancer therapy

Abstract

Proteasome inhibitor Bortezomib/Velcade has emerged as an effective anticancer therapy for the treatment of relapsed and/or refractory multiple myeloma (MM), but prolonged treatment can be associated with toxicity and development of drug resistance. In this review, we discuss the recent discovery of a novel proteasome inhibitor, NPI-0052, that is distinct from Bortezomib in its chemical structure, mechanisms of action, and effects on proteasomal activities; most importantly, it overcomes resistance to conventional and Bortezomib therapies. In vivo studies using human MM xenografts shows that NPI-0052 is well tolerated, prolongs survival, and reduces tumour recurrence. These preclinical studies provided the basis for Phase-I clinical trial of NPI-0052 in relapsed/ refractory MM patients. The systemic regulation of protein synthesis and protein degradation is essential for normal cellular functioning. The ubiquitinproteasome pathway mediates intracellular protein degradation: first, protein is marked with a chain of small polypeptides called ubiquitin; E1 ubiquitin enzyme then activates ubiquitin and links it to the ubiquitin-conjugating enzyme E2 in an ATP-dependent manner; E3 ubiquitin ligase then links the ubiquitin molecule to the protein; a long polypeptide chain of ubiquitin moieties is formed; and finally, a multi-enzyme proteolytic complex 26S proteasome degrades protein into small fragments in an ATPdependent manner.

Analysis of changes in the proteome of HL-60 promyeloid leukemia cells induced by the proteasome inhibitor PSI

“…In addition, bortezomib has entered various clinical trials since then in which the potency of this anti-cancer drug either as single agent or in combination with other chemotherapeutics is being evaluated [16]. The success of bortezomib, which has established the principle of proteasome inhibition as a novel cancer treatment modality, has further promoted the development of more novel proteasome inhibitors, such as NPI-0052 [17,18] or PR-171 [19], which show increased activity, reduced toxicity and enhanced oral availability (NPI-0052).…”

Preclinical animal models of multiple myeloma

“…These models offer the opportunity to evaluate homing of MM cells to the bone marrow 8 and to test the efficacy of therapeutics against human myeloma in vivo. 24,25 The utility of xenograft models for the evaluation of myeloma cell interactions within the bone marrow microenvironment, however, is not fully understood, as the myeloma bone marrow microenvironments induced in these animals are not easily translated to humans. A recent study using bioengineered nanoparticles capable of targeting bone and delivering pharmaceuticals to the bone marrow space demonstrated that pre-treatment of NOD/SCID animals with bone-targeting nanoparticles altered the bone marrow niche, delaying engraftment of luciferase-tagged MM1.S (human) MM cells following intravenous injection.…”

Oxidative Stress by Targeted Agents Promotes Cytotoxicity in Hematologic Malignancies

“…One of the newer, clinically relevant proteasome inhibitors, NPI-0052, is structurally reminiscent of lactacystin, the first described chemical inhibitor of the 20S proteasome (11). Lactacystin is a microbial metabolite isolated from Streptomyces and, despite significant potency, is not suitable for clinical use.…”