VR23 is a small molecule inhibitor which targets β2 of the 20Sproteasome with IC50 of 1 nM and can induce apoptosis of cancer cells via cyclin E–mediated centrosome amplification.
Proteasomes play a critical role in regulating the level of cellular proteins and recycling damaged and misfolded proteins, as well as regulating the proliferation and survival of cancer cells. VR23 is a small molecule inhibitor of trypsin-like proteasomes, chymotrypsin-like proteasomes, and caspase-like proteasomes with IC50 values of 1nM, 50-100nM, and 3μM, respectively[2]. In vitro, VR23 inhibited proliferation of the multiple myeloma cell lines RPMI 8226 and KAS6/1 with IC50 values of 2.94μM and 1.46μM, respectively. VR23 also inhibited proliferation of the noncancer cell lines 184B5 and MCF10A with IC50 values of 9.00μM and 12.30μM, respectively. A clonogenic assay showed that very few MCF7 cells survived for 2 weeks at 1.5μM of VR23. Treatment of MCF7 cells with 2.7μM or 8.0μM of VR23 resulted in 23.7% or 38.2% sub-G1 DNA content within 48 hours after treatment, respectively. These data demonstrated that the noncancer MCF10A was more resistant to VR23 compared to MCF7 cells. In vivo, intraperitoneal administration of VR23 at 30mg/kg twice per week for 3 weeks reduced tumor size in ATH490 athymic mice engrafted with MDA-MB-231 metastatic breast cancer cells. VR23 also reduced tumor size in ATH490 athymic mice engrafted with RPMI8226 multiple myeloma cells, suggesting the antitumor activity of VR23 is not limited to metastatic breast cancer[2].
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