Cell Death and Deubiquitinases: Perspectives in Cancer

Table 3

Drugs targeting the DUBs.

Drug	Target	Outcome	Comments	Reference
Multiple Targets
Betulinic acid	Multiple DUBs	Accumulates poly-Ub targets and enhances their degradation via UPS; inhibits PCa cell proliferation and induces apoptosis	Specific in action against cancer cells without affecting normal cells	[5]
Curcusone D	Multiple DUBs	ROS-induced inhibition of DUBs; growth inhibition and apoptosis of multiple myeloma (MM) cells	Shows synergistic effect with Bortezomib in MM	[6]
PR-619	Multiple DUBs	Accumulates polyubiquitinated proteins and enhances proteasomal activity	Small molecule inhibitor	[7]
Cyclopentenone prostaglandins, dibenzylideneacetone, curcumin, and shikoccin	Cellular isopept-idase	Cell death in colon cancer cells	Very broad spectrum	[8]
b-AP15	UCH-L5 USP14	Blocks proteasome function and promotes tumor cell apoptosis in preclinical models	High specificity	[9]
P22077	USP7; USP47	Induction of apoptosis involving p53 by multiple pathways (Mdm2, Claspin, Tip60, etc.)	Specific small molecule inhibitor	[7, 134]
WP1130	USP5; USP9X; USP14; UCH-L1; UCH-37	Decreased Mcl-1, increased p53, stops cell proliferation and induces death in multiple myeloma (MM) and mantle cell lymphoma (MCL)	Poor solubility and pharmacokinetics	[10]
G9; (a WP1130 derivative)	USP9X; USP24	Decreased Mcl-1, increased p53, induces cell death in MM, MCL and melanoma	Better solubility and lesser toxicity than WP1130	[10]
Specific Targets
3-Amino-2-keto-7H-thieno[2,3-b]pyridin-6-one derivatives	UCH-L1	Moderately potent inhibitors	Does not show activity against other cysteine hydrolases	[11]
Pimozide; and GW7647	USP1	Shows synergistic effect with cisplatin in cytotoxicity of NSCLC	Specificity is high	[12]
2-cyanopyrimidine and triazine; derivatives	USP2	Specific biological data is absent	—	[8]
HBX 41,108	USP7	Activates p53 and induces apoptosis in cancer cells	Shows some cross-reactivity	[13]
HBX 19,818; and HBX 28,258	USP7	Leads to cell cycle arrest in HCT116 cells	Specific inhibition of catalytic activity	[14]
Spongiacidin C	USP7	—	A natural pyrrole alkaloid	[15]
HBX 90,397; and HBX 90,659	USP8	Induces G1 arrest and inhibits cell growth in HCT116 and PC3	Small molecule inhibitor	[16]
9-oxo-9; H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile; and analogs	USP8	Antiproliferative and proapoptotic in cancer cell lines	Selective inhibitor	[17]
1-[1-(4-fluorophenyl)-2,5-dimethylpyrrol-3-yl]-2-pyrrolidin-1-ylethanone)-IU1	USP14	Enhances proteasome function and accelerates proteolysis	Small molecule inhibitor	[18]