Table 3.

Small-molecule inhibitors of the deubiquitinases (DUBs).

Compound Name	UPS Target	Mode of Action	Current Clinical Stage	Cancer Models Targeted in Preclinical Studies	Clinical Trial Cancer Targets
HBX 41108, HBX 19818, HBX 28258	USP7	Covalently binds USP7 active site, increasing p53	Preclinical	Colon cancer cell lines [249,252]	N/A
P5091	USP7 and USP47	Dual inhibitor of USP7 and USP47	Preclinical	MM cells, bortezomib-resistant MM, and B-cell leukemia mouse models [253]	N/A
P50429, P22077	USP7	Irreversibly bind catalytic cysteine residue of USP7	Preclinical	Colon cancer cell line [254], neuroblastoma xenograft [255]	N/A
Compound 4	USP7	Selectively binds USP7 allosteric site	Preclinical	Leukemia, prostate adenocarcinoma cell lines [259]	N/A
GNE-6640, GNE-6776	USP7	Binds novel USP7 functional site	Preclinical	Colon cancer cells [260]	N/A
XL188	USP7	Non-covalent inhibition of USP7 active site, causing accumulation of p53 and p21	Preclinical	Breast cancer and MM cell lines [261]	N/A
FT671, FT827	USP7	Allosteric USP7 inhibition	Preclinical	Colon cancer, osteosarcoma cell lines, MM cells, and xenografts [262]	N/A
Pimozide and GW7647	USP1/UAP1 complex	Non-competitive inhibition of USP1	Preclinical	NSCLC cells [263]	N/A
IU1, IU1-47, 1B10, IU1-248	USP14	Binds USP14 steric site	Preclinical	N/A	N/A
b-AP15	USP14 and UCHL5	Blocks 19S DUB activity	Preclinical	Solid tumors, MM [40,72,73,74]	N/A
VLX1570	USP14 and UCHL5	b-AP15 analog, also blocks 19S DUBs	Preclinical (Phase 1/2 terminated)	MM [42]	Multiple Myeloma (MM)
Capzimin, 8TQ	Rpn11	Specific inhibitors of Rpn11	Preclinical	Leukemia, NSCLC, breast cancer [79]	N/A
Thiolutin, SOP11	Rpn11 (nonspecific)	Non-specifically inhibits JAMM-family DUBs	Preclinical	Colon cancer, bortezomib-resistant RPE cells [80]	N/A
Celasterol, mangaferin	UCHL1	Reversible inhibitors of UCHL1	Preclinical	N/A	N/A
LDN-57444, LDN-Pox	UCHL1	Incorporation of LDN-57444 in Pox micelle delivery system inhibits UCHL1 in cells	Preclinical	Oral squamous cell carcinoma cell line [264]	N/A
6RK73 and 8RK64	UCHL1	Cell penetrable probes bind UCHL1 active site cysteine in activity-dependent manner	Preclinical	N/A	N/A
WP1130	USP9X	Inhibits USP9X, UCHL, and USP14 to a degree	Preclinical	CML, melanoma, glioblastoma, myeloproliferative disorders [44,75,76], MCL [77], AML [78]	N/A
EOAI3402143 (G9)	USP9X/USP24 (and partially USP5)	WP1130 analog	Preclinical	AML [78], MM [265], melanoma [76]	N/A
FT709	USP9X	Competitively binds USP9X active site	Preclinical	Colon cancer cell line [266]	N/A
OTUB2-COV-1	OTUB2	Covalent OTUB2 inhibitor	Preclinical	N/A	N/A
BC-1471	STAMBP	Inhibits STAMBP, prevents interaction with NALP7	Preclinical	N/A	N/A