Velcade competition -- keeping an eye on NPI-0052:
>>Mol Cancer Ther. 2006 Jul;5(7):1836-43.
The proteasome inhibitor NPI-0052 is a more effective inducer of apoptosis than bortezomib in lymphocytes from patients with chronic lymphocytic leukemia.
Ruiz S, Krupnik Y, Keating M, Chandra J, Palladino M, McConkey D.
Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Box 173, 1515 Holcombe Boulevard, Houston, TX 77030. dmcconke@mdanderson.org.
Proteasome inhibitors are potent inducers of apoptosis in isolated lymphocytes from patients with chronic lymphocytic leukemia (CLL). However, the reversible proteasome inhibitor bortezomib (PS-341; Velcade) did not display substantial antitumor activity in CLL patients. Here, we compared the effects of bortezomib and a new irreversible proteasome inhibitor (NPI-0052) on 20S chymotryptic proteasome activity and apoptosis in isolated CLL cells in vitro. Although their steady-state (3 hours) IC(50)s as proteasome inhibitors were similar, NPI-0052 exerted its effects more rapidly than bortezomib, and drug washout experiments showed that short exposures to NPI-0052 resulted in sustained (>/=24 hours) 20S proteasome inhibition, whereas 20S activity recovered in cells exposed to even 10-fold higher concentrations of bortezomib. Thus, brief (15 minutes) pulses of NPI-0052 were sufficient to induce substantial apoptosis in CLL cells, whereas longer exposure times (>/=8 hours) were required for commitment to apoptosis in cells exposed to equivalent concentrations of bortezomib. Commitment to apoptosis seemed to be related to caspase-4 activation, in that cells exposed to bortezomib or NPI-0052 could be saved from death by addition of a selective caspase-4 inhibitor up to 8 hours after drug exposure. Our results show that NPI-0052 is a more effective proapoptotic agent than bortezomib in isolated CLL cells and suggest that the chemical properties of NPI-0052 might also make it an effective therapeutic agent in CLL patients.<<
Some explanation as to why NPI-0052 might be better:
>>Nereus Pharmaceuticals has NPI-0052 in preclinical development. The company, based in San Diego, looks for its compounds under the sea, and NPI-0052 (salinosporamide) was isolated from a marine microorganism. In vitro data presented at ASH by Nereus and Harvard Medical School's Dana-Farber Cancer Institute showed that the compound was active in multiple myeloma cells resistant to Velcade, as well as dexamethasone and doxorubicin. While the exact mechanisms still are under investigation, Nereus Chief Technical Officer Michael Palladino said that they might be due to the differential targeting of the three proteasome pathways by the two compounds.
While both Velcade and NPI-0052 are active against the chymotryptoic component of the proteasome, only NPI-0052 is active against the tryptic component, and it also might affect the caspase component of the proteasome more strongly than Velcade. Based on its in vitro and animal data, Nereus hopes to file an investigational new drug application for NPI-0052 within a year.<<
rigel.com
The article is from December '04. NPI-052 is probably in the clinic now, but still a fairly distant threat. Unless they manage to get an NDA done on PII data, like Velcade.
Cheers, Tuck |
