TY - JOUR
T1 - Specific cell-permeable inhibitor of proteasome trypsin-like sites selectively sensitizes myeloma cells to Bortezomib and Carfilzomib
AU - Mirabella, Anne C.
AU - Pletnev, Alexandre A.
AU - Downey, Sondra L.
AU - Florea, Bogdan I.
AU - Shabaneh, Tamer B.
AU - Britton, M.
AU - Verdoes, Martjin
AU - Filippov, Dmitri V.
AU - Overkleeft, Herman S.
AU - Kisselev, Alexei F.
PY - 2011/5/27
Y1 - 2011/5/27
N2 - Proteasomes degrade the majority of proteins in mammalian cells, are involved in the regulation of multiple physiological functions, and are established targets of anticancer drugs. The proteasome has three types of active sites. Chymotrypsin-like sites are the most important for protein breakdown and have long been considered the only suitable targets for antineoplastic drugs; however, our recent work demonstrated that inhibitors of caspase-like sites sensitize malignant cells to inhibitors of the chymotrypsin-like sites. Here, we describe the development of specific cell-permeable inhibitors and an activity-based probe of the trypsin-like sites. These compounds selectively sensitize multiple myeloma cells to inhibitors of the chymotrypsin-like sites, including antimyeloma agents bortezomib and carfilzomib. Thus, trypsin-like sites are cotargets for anticancers drugs. Together with inhibitors of chymotrypsin- and caspase-like sites developed earlier, we provide the scientific community with a complete set of tools to separately modulate proteasome active sites in living cells.
AB - Proteasomes degrade the majority of proteins in mammalian cells, are involved in the regulation of multiple physiological functions, and are established targets of anticancer drugs. The proteasome has three types of active sites. Chymotrypsin-like sites are the most important for protein breakdown and have long been considered the only suitable targets for antineoplastic drugs; however, our recent work demonstrated that inhibitors of caspase-like sites sensitize malignant cells to inhibitors of the chymotrypsin-like sites. Here, we describe the development of specific cell-permeable inhibitors and an activity-based probe of the trypsin-like sites. These compounds selectively sensitize multiple myeloma cells to inhibitors of the chymotrypsin-like sites, including antimyeloma agents bortezomib and carfilzomib. Thus, trypsin-like sites are cotargets for anticancers drugs. Together with inhibitors of chymotrypsin- and caspase-like sites developed earlier, we provide the scientific community with a complete set of tools to separately modulate proteasome active sites in living cells.
UR - http://www.scopus.com/inward/record.url?scp=79957477617&partnerID=8YFLogxK
UR - http://dx.doi.org/10.1016/j.chembiol.2011.02.015
U2 - 10.1016/j.chembiol.2011.02.015
DO - 10.1016/j.chembiol.2011.02.015
M3 - Article
SN - 1074-5521
VL - 18
SP - 608
EP - 618
JO - Chemistry & Biology
JF - Chemistry & Biology
IS - 5
ER -