Table 4.

USP inhibitors involve in overcoming drug resistance of cancers

Target	Inhibitor	Chemical structure	Enzyme activity/IC50	Cancer type	Biological mechanism in drug resistance	Reference
USP7	P22077		USP7/USP47 (8µM)	Neuro-blastoma	P22077 enhances the cytotoxic effects of Dox and etoposide in NB cells with an intact USP7-HDM2-p53 axis.	[84]
				HCC	P22077 induces cell death, inhibits cell proliferation and migration and decreases cell sensitivity to chemotherapy.	[82]
				Pancreatic cancer	P22077 reduces protein synthesis, and alters the extracellular space matrix to overcome Dox resistance.	[83]
				Acute myeloid leukemia	P22077 reduces cell proliferation, blocks DNA replication progression and increases the killing effect of cytarabine.	[254]
				Lung cancer	Combination treatment with the mitotic kinase PLK1 inhibitor volasertib and the P22077 shows a strong synergism through down-regulation of MDR1/ABCB1 in paclitaxel-resistant lung cancer.	[104]
				Chronic lymphocytic leukemia	P22077 eliminates leukemia stem/progenitor cells and overcomes imatinib resistance through destabilizing YB-1 and inhibiting DDR.	[154]
	P5091		USP7(4.2µM)	Multiple myeloma	P5091 induces apoptosis in MM cells and overcomes BTZ resistance. Combining P5091 with lenalidomide, HDAC inhibitor SAHA, or dexamethasone triggers synergistic anti-MM activity.	[177]
				Multiple myeloma	P5091 and NEK2 inhibitor together overcome BTZ resistance through regulating NF-κB signaling pathway and the PP1α/AKT axis.	[175]
				Multiple myeloma	RRx-001 plus P5091 triggered synergistic anti-MM activity and overcome BTZ resistance.	[255]
				Lung neuro-endocrine tumor	P5091 sensitizes lung neuroendocrine tumor cells to PARP inhibitor by lowering CCDC6 and HR repair.	[147]
				Prostate cancer	P5091 accelerates the degradation of AR and CCDC6, sensitizing cancer cells to PARP-inhibitors.	[145]
				Lewis lung carcinoma	P5091 upregulates PD-L1, deregulates PD-1 and reprogramming TAMs in TME, enhancing the anti-tumor immune response.	[209]
	GNE6776		USP7(1.34µM)	TNBC	GNE-6776 increased apoptosis in chemoresistant TNBC cells through inhibiting the interaction between USP7 and ABCB1.	[93]
	HBX19818		USP7(4.2µM)	Chronic lymphocytic leukemia	P22077 sensitizes p53-defective, chemoresistant CLL cells to chemotherapeutic agents through the accumulation of DNA damage.	[172]
	Compound41		USP7(0.44nM)	NSCLC	Compound 41 resensitizes MYCN-overexpressing chemoresistant NSCLC cells to cisplatin and etoposide treatment by decreasing N-MYC protein and increasing apoptosis.	[256]
USP1	GW7647		USP1/UAF1 (5µM)	NSCLC	GW7647 in combination with cisplatin together enhances monoubiquitylation of PCNA and FANCD2 to promote therapeutic efficacy.	[40]
	Pimozide		USP1/UAF1 (1.96µM)	Lung cancer	The combination of pimozide and MAST1 inhibitor lestaurtinib sensitizes cells to cisplatin by reducing MAST1 expression and subsequent phosphorylation of MEK1 and ERK.	[43]
				B-cell lymphoma	Pimozide shows a synergetic effect with etoposide in rituximab/chemotherapy resistant cells through destabilization of MAX.	[257]
	SJB3-019A (SJB)		USP1/UAF1 (781nM)	Multiple myeloma	Combining SJB with the ACY-1215, BTZ, lenalidomide, or pomalidomide shows synergistic cytotoxicity through activating apoptosis, inhibiting DNA repair and HR, as well as the downregulating stem cell renewal.	[258]
	ML323		USP1/UAF1 (76nM)	NSCLC	ML323 enhances the cytotoxicity of cisplatin in resistant NSCLC by inhibiting the deubiquitylation of PCNA and FANCD2.	[38]
				Breast cancer and ovarian cancer	ML323 kills BRCA1 deficient cells that have acquired resistance to PARP inhibitors due to replication fork stabilization.	[143]
USP13	Spautin-1		USP10/USP13, (0.6-0.7µM)	Ovarian cancer	Spautin-1 disrupts the formation of RAP80-BRCA1 complex foci and impairs DDR, thus rendering cancer cells sensitive to olaparib.	[137]
				Gastro-intestinal stromal tumor	Spautin-1 induces the decay of ATG5 and co-administration of spautin-1 with 3-methyladenine enhances the therapeutic efficacy of imatinib.	[158]
USP14	b-AP15		USP14/UCHL5 (2.1µM)	Waldenström macro-globulinemia	b-AP15 can induce apoptosis in cells overexpressing Bcl-2 and lacking functional p53 to overcome BTZ resistance.	[259]
	VLX1570		USP14/UCHL5 (10µM)	Waldenström macro-globulinemia	VX1570 promotes rapid and tumor-specific apoptosis in WM cells resistant to BTZ or ibrutinib.	[173]
	IU-1		USP14(4.7µM)	Colorectal cancer	IU1 combined with anti-PD-1 enhances the anti-tumor response through regulating the infiltration ratio of CD8+ T cells and FOXP3+ Treg cells, also inhibiting IDO1-mediated immune suppression.	[228]
USP8	DUBs-IN-2		USP8(0.93µM)	-	DUBs-IN-2 leads to the upregulation of PD-L1, triggering immune responses and antigen presentation through TRAF6-NF-κB signaling pathway to enhance the efficacy of anti-PD-1/PD-L1 immunotherapy.	[207]
				Pancreatic cancer	The combination therapy of DUBs-IN-2 and anti-PD-L1 suppress tumor growth, which is mediated by the activating anti-tumor immunity relies on the PD-L1 pathway and CD8+ T cells.	[206]
	9-ethyloxyimino-9H-indeno[1,2-b] pyrazine-2,3-dicarbonitrile		USP8(<1µM)	NSCLC	This inhibitor suppresses the expression of multiple RTKs in gefitinib-resistant NSCLC cells by enhancing the colocalization between Ub and target RTKs.	[196]
				HCC	This inhibitor enhances the efficacy of DOX or sorafenib by reducing the expression levels of RTKs.	[90]