Table 2.

Inhibitors of the constitutive proteasome complex.

Compounds	Target	Modes of Action	Targeted Cancer Types in Preclinical Studies	Targeted Cancer Types in Clinical Studies or Therapies	Other Disease	Ref.
Inhibitors targeting 20S core particle of the proteasome
Bortezomib	β5 > β1	Inhibits the chymotrypsin-like activity of the proteasome by reversible binding to the β5 subunit thus inhibits proteasomal activity and leads to accumulation of polyubiquitinated proteins in cells		Multiple Myeloma Mantle cell lymphoma Acute myeloid leukemia lung cancers hepatocellular carcinoma Intrahepatic Cholangiocarcinoma Relapsed/Refractory Multiple Myeloma Neuroblastoma Colorectal Cancer Head and Neck Cancer Thyroid Carcinoma More cases to https://clinicaltrials.gov	Haemolytic anaemia Immune thrombocytopenia Lung disease Cold agglutinin disease Amyloidosis Macroglobulinemia	[98,99,100,101,102,103,104]
Carfilzomib	β5	Covalent bonds to proteasome catalytic subunits, predominantly β5		Multiple myeloma Relapsed and/or refractory multiple myeloma Lymphoma Chronic lymphocytic leukemia Thyroid cancer Refractory renal cell carcinoma Lung cancer More cases to https://clinicaltrials.gov	Pulmonary arterial hypertension	[105,106,107,108,109,110,111,112]
Ixazomib	β5 > β1	First orally bioavailable proteasome inhibitor drug, predominantly targeting β5		Multiple myeloma Refractory or relapsed multiple myeloma Acute myeloid leukemia Relapsed refractory acute myeloid leukemia Hodgkin and T-cell lymphoma Mantle cell lymphoma Non-hematologic malignancies lymphoma Breast cancer Glioblastoma Bladder cancer Renal cell carcinoma Waldenstrom macroglobulinemia Solitary osseous plasmacytoma More cases to https://clinicaltrials.gov	Al amyloidosis Autoimmune cytopenia HIV Lupus nephritis Kidney diseases	[113,114,115,116,117,118,119]
Oprozomib	β5 > β1	A structural homologue of CFZ, orally available and applied to patients with relapsed after receiving BTZ- and CFZ-based therapies		Multiple Myeloma Relapsed and/or refractory multiple myeloma Hepatocellular carcinoma Waldenstrom macroglobulinemia Non-central nervous system malignancies	No reported applications	[120,121,122,123]
Marizomib	β5 > β2 > β1	Irreversibly inhibits the activity of proteasome and more effectively induces apoptosis in tumor cells from MM and chronic lymphocytic leukemia patients, while shows a lower toxicity to normal cells than BTZ		Multiple Myeloma Relapsed and/or refractory multiple myeloma Ependymoma Non-small Cell Lung Cancer Pancreatic Cancer Melanoma Lymphoma Glioblastoma	No reported applications	[124,125,126,127,128]
Inhibitors targeting 19S regulatory particle of the proteasome
IU1 IU1-47	USP14	Targets the thiol group in the active cysteine site in USP14 protease and significantly decrease cell proliferation, migration, and invasion.	Breast cancer Lung cancer		No reported applications	[129,130]
b-AP15	USP14 UCHL5	Targets both UCHL5 and USP14, disrupts the aggresome formation in cancer cells by activating caspase to further induce apoptosis relating to an upregulation of oxidative stress	Acute myeloid leukemia Multiple myeloma Large b cell lymphoma Mantle cell lymphoma Neuroblastoma Prostate cancer Breast cancer Lung cancer Head and neck cancer Colon cancer Ovarian cancer		No reported applications	[131,132,133,134,135,136,137,138,139,140,141]
VLX1570	USP14 UCHL5	An analog of b-AP15, more effective than b-AP15 in inhibiting tumor progression	See targeted cancer types of b-AP15	Multiple Myeloma	No reported applications	[142,143,144,145]
RA-9	USP14	Reacts with the sulfurs in the active site cysteine and inhibits proteasome-associated DUBs	Breast cancer Ovarian cancer Cervical cancer		Rheumatoid arthritis	[146,147]
WP1130	UCHL5 USP14 USP9X	Directly inhibits USP9X in addition to UCHL5 and USP14, induces apoptosis and prevents drug resistance in malignancies through Mcl-1 degradation	Acute myeloid leukemia Chronic myelogenous leukemia Human mesothelioma Lung cancer Colon cancer Prostate cancer Hepatocellular carcinoma		No reported applications	[148,149,150,151,152,153,154]
OPA	RPN11	A zinc ion chelator, inhibits the activity of RPN11 metal-containing enzymes of 19S and induces apoptosis including cell lines which are BTZ resistant	Multiple myeloma Hepatocellular carcinoma Cervical cancer Breast carcinoma		Sarcoidosis	[155,156,157,158,159,160,161]
8TQ	RPN11	A strong RPN11-specific inhibition of proteasome 19S subunit and is a potent apoptosis inducer in MM cells	Lung carcinoma Colon cancer		No reported applications	[162]
Thiolutin	RPN11	The reduced form of Thiolutin is an inhibitor of JAB1/MPN/Mov34 (JAMM) domain-containing metalloprotease RPN11 by chelating Zn2+-ions which is specifically toxic to cancer cells by hampering protein turnover	Only in cell free system		No reported applications	[163]