Table 1.

Inhibitors targeting E1s, E2s and E3s.

Compounds	Target	Modes of Action	Targeted Cancer Types in Preclinical Studies	Targeted Cancer Types in Clinical Studies or Therapies	Other Disease	Ref.
Inhibitors targeting E1s of the UPS
PYR-41	UBA1	Irreversibly binds to the active cysteine in UBA1 and kill tumor cells by inhibiting cytokine-induced NF-κB activation, and promoting p53 accumulation	Prostate cancer Thyroid cancer		Hypertensive heart diseases/ Sepsis	[1,2,3,4,5,6]
MLN4924	NAE	Covalently binds the nucleotide-binding site of NAE and generates a NEDD8-MLN4924 adduct that further undermines protein turnover leading to apoptosis in cancer cells	Liver cancer Pancreatic cancer	Acute Myelogenous Leukemia (AML) Multiple Myeloma Lymphoma Melanoma Lung Cancer Mesothelioma	Pulmonary inflammation/ Ipopolysaccharide-induced kidney damage/ Spinal cord ischemia-reperfusion injury/ Myelodysplastic Syndromes	[7,8,9,10,11,12,13,14,15,16]
Inhibitors targeting E2s of the UPS
CC0651	hCdc34	An allosteric inhibitor of human E2 enzyme hCdc34, causes large-scale structural rearrangements and affects the discharge of ubiquitin to acceptor lysine residues	Prostate cancer Colon cancer		No reported applications	[17]
NSC697923	Ubc13–Uev1A E2	Blocks the formation of the E2–Ub thioester conjugate and inhibits the activation of NF-κB signaling leading to reduced proliferation and cell viability	Melanoma B-cell lymphoma Neuroblastoma Colorectal Cancer		Diabetic nephropathy	[18,19,20,21,22]
Inhibitors targeting E3s of the UPS
Nutlin-3a	Mdm2	Competitively binds the Mdm2-P53 interacting site, activates P53 pathway, and thus results in cell cycle arrest, cell death, and growth inhibition	Acute/Chronic lymphocytic leukemia Hodgkin lymphoma Pancreatic cancer Glioblastoma Sarcoma Colon cancer Breast cancer Ovarian cancer Lung cancer Ewing sarcoma		Pulmonary arterial hypertension	[23,24,25,26,27,28,29,30,31,32,33,34,35]
RG7388 (R05503781) RG7112 (R05045337)	Mdm2	The derivatives of nutlin-3a and Inhibits Mdm2-P53 binding site		Acute myeloid leukemia Relapsed or refractory Acute myeloid leukemia Multiple myeloma Relapsed multiple myeloma Glioblastoma Ovarian cancer Childhood sarcoma Neuroblastoma Breast cancer Lung cancer	Polycythemia vera/ Essential Thrombocythemia	[36,37,38,39,40,41,42,43]
GDC-0152 SM-406	IAPs	Potent and orally bioavailable SMAC mimetic and antagonists of the inhibitor of IAPs with highly effective in induction of apoptosis in xenograft tumors, and is capable of inhibition of tumor growth	Osteosarcoma Leukemia Thyroid cancer Glioblastomas Breast cancer		No reported applications	[44,45,46,47,48]
SCF-12	FBW7	Blocks the substrate-binding pocket and impedes substrate recognition via inhibiting Cdc4 thus hinders tumor progression in colon and prostate cancers	Colon cancer Prostate cancer		No reported applications	[49]
Oridonin	FBW7	Targets FBW7-c-Myc pathway and activates GSK-3, decreases c-Myc and induces apoptosis in leukemia and lymphoma cells	Myelogenous leukemia Breast cancer		Myocardial ischemia Reperfusion injury	[50,51,52]
Compound #25	SKP2	Directly binds SKP2, selectively suppresses Skp2 E3 ligase activity and exhibits potent antitumor activities in multiple animal models	Prostate cancer		No reported applications	[53]
NAHA	Cdc20	Decreases Cdc20 expression and inhibits tumor proliferation in vitro and in vivo associated with the induction of apoptosis	Breast cancer		No reported applications	[54]
CM11-1	E6AP	Acts as an E6AP inhibitor that prevents polyubiquitination of Prx1 and p53 in E6-independent and E6-dependent manner	Only in RaPID System cell free system		No reported applications	[55]