Carfilzomib (PR-171)

Carfilzomib is an irreversible proteasome inhibitor with an IC50 of 5 nM in ANBL-6 and RPMI 8226 cells.

Carfilzomib displays preferential in vitro inhibitory potency against the ChT-L activity in the β5 subunit, with over 80% inhibition at doses of 10 nM and above and little or no effect on the PGPH and T-L activities at doses up to 100 nM. Carfilzomib decreases the viability of ANBL-6, RPMI 8226 cells, U266 and KAS-6/1 cells with an IC50 less than 5 nM. Carfilzomib overcome Dex resistance, in that MM1.R cells reveals an IC50 of 15.2 nM, less than the value of 29.3 nM for parental MM1.S cells[1]. Co-treatment with carfilzomib and HDACIs leads to synergistic induction of cell death in various mantle cell lymphoma lines and primary mantle cell lymphoma cells. Combined treatment with carfilzomib or ONX0912 with vorinostat in HF-4B and Granta cells sharply increases caspase activation, PARP cleavage, JNK activation, MnSOD2 induction, and DNA damage[2].

Carfilzomib (2.0 mg/kg, i.v.) in conbination with 70 mg/kg vorinostat virtually abrogates tumor growth in Granta-luciferace cell xenograft flank model. Combined treatment results in a pronounced reduction in bioluminescence compared to animals treated with single agents or controls with minimal toxicity[2].

References:
[1]. Kuhn DJ, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007 Nov 1;110(9):3281-90.
[2]. Dasmahapatra G, et al. Carfilzomib interacts synergistically with histone deacetylase inhibitors in mantle cell lymphoma cells in vitro and in vivo. Mol Cancer Ther. 2011 Sep;10(9):1686-97.