Table 2.

Small-molecule inhibitors of the E3 ubiquitin ligases.

Compound Name	UPS Target	Mode of Action	Current Clinical Stage	Cancer Models Targeted in Preclinical Studies	Targeted Cancer Types in Clinical Trials	Published Clinical Trial Results
MDM2 inhibitors
Nutlin-3	MDM2	Competitive inhibitor of p53 binding site on MDM2	Preclinical	AML [101], hematologic malignancies [102,103,104,105], breast cancers [106,107], glioblastoma [108]	N/A	N/A
RG7112 (RO5045337)	MDM2	Nutlin derivative, inhibits MDM2–p53 binding site	Phase 1	Cancer cell lines expressing wild-type p53 [109]	Leukemia, hematologic neoplasms, liposarcoma, advanced solid tumors, myeloproliferative neoplasms	[110,111,112]
RG7388 (RO5503781, Idasanutlin)	MDM2	Nutlin derivative, inhibits MDM2–p53 binding site	Phase 2 (Phase 3 terminated)	Cancer cell lines expressing wild-type p53, osteosarcoma xenografts [113]	AML, ALL, solid tumors, neuroblastoma, plasma cell myeloma, breast cancer, PV and ET, and more	[114,115,116]
MI-77301 (SAR405838)	MDM2	Selectively binds MDM2–p53 binding site, improved affinity via MDM2 N-term refolding	Phase 1	Leukemia, osteosarcoma, prostate and colon cancer cell lines [117]	Malignant neoplasms, advanced solid tumors, lymphoma	[118,119]
MK-8242 (SCH-900242)	MDM2	Oral MDM2–p53 inhibitor	Phase 1	N/A	AML, advanced solid tumors	[120,121]
AMG 232	MDM2	Inhibits MDM2–p53 interaction with improved potency due to hydrophobic interactions with MDM2 “glycine shelf”	Phase 1	Various tumor cell lines and xenografts [122,123,124]	AML, advanced solid tumors, glioblastoma, gliosarcoma, metastatic melanoma, MM, and more	[125,126]
Ds3032b (Milademetan)	MDM2	Oral MDM2–p53 inhibitor	Phase 2	Neuroblastoma [127], BCL [10]	Myeloma, AML, recurrent/refractory myeloid leukemia, advanced solid tumors, lymphomas	[128,129]
HDM 201 (Siremadlin)	MDM2	Binds to MDM2, inhibits interaction with p53	Phase 2	Wild-type-p53 cancer cell lines [130]	AML, colorectal cancer, liposarcoma, malignant solid tumors, and more	[131,132]
APG-115	MDM2	Oral MDM2–p53 inhibitor	Phase 2	Osteosarcoma xenografts [133]	AML, T-prolymphocytic leukemia, liposarcoma, advanced solid tumors, melanoma, salivary gland cancer	[134,135]
CGM097	MDM2	MDM2–p53 inhibitor	Phase 1	Colorectal cancer, osteosarcoma cells [136]	Solid tumors with wild-type p53	N/A
PRIMA1, APR-246	MDM2	Binds core domain of p53, preventing MDM2 association	Phase 3	Osteosarcoma, NSCLC, adenocarcinoma cell lines and xenografts [137,138], myeloma [139]	AML, myeloid malignancies, NSCLC, gastric cancer, esophageal carcinoma, non-Hodgkin’s lymphoma, CLL, MCL, hematologic neoplasms, and more	[140]
MI-63	MDM2	Binds MDM2, preventing p53 association	Preclinical	Prostate cancer cells with wt-p53 [141]	N/A	N/A
MI-219	MDM2	Binds MDM2, preventing p53 association; can also induce degradation of MDMX.	Preclinical	Various solid cancer cell lines, osteosarcoma xenografts [142]	N/A	N/A
Sempervirine	MDM2	MDM2–p53 inhibitor	Preclinical	Wt-p53 mouse embryonic fibroblast cell model [143]	N/A	N/A
RITA	MDM2	Binds wt-p53, preventing association with MDM2	Preclinical	Fibrosarcoma and colon cancer cell lines and wt-p53 tumor xenografts [144]	N/A	N/A
Syl-155	MDM2	Competitively inhibits MDM2–p53 binding	Preclinical	Wt-p53 fibrosarcoma cell line [145]	N/A	N/A
HLI373	MDM2	Competitively inhibits MDM2–p53 binding	Preclinical	Colon carcinoma cell line, wt-p53 transformed MEF cell model [146]	N/A	N/A
MEL24	MDMX/MDM2	Inhibits E3 ligase activity of MDM2–MDMX complex	Preclinical	Various wt-p53 cancer cell lines [147]	N/A	N/A
NSC207895 (XI-006)	MDMX	Represses MDMX transcription, activates p53 pathway	Preclinical	Various solid tumor cell lines [148]	N/A	N/A
CRL/SCF RING E3 inhibitors
Oridonin	FBW7	Promotes proteasomal degradation of c-Myc via FBW7 agonism	Preclinical	Leukemia and lymphoma cell lines [149]	N/A	N/A
SCF-I2	FBW7	Blocks substrate-binding pocket, inhibits Cdc4, prevents substrate recognition	Preclinical	Colon and prostate cancer cell lines [150]	N/A	N/A
SMER3	Met30	Directly binds Met30, preventing association with SCF complex	Preclinical	N/A	N/A	N/A
Compound A	SKP2	Prevents association of SKP2 with SCF complex, results in accumulation of p27	Preclinical	MM cell lines, primary hematological malignancy cells [151]	N/A	N/A
SMIP004	SKP2	Downregulates SKP2, stabilizes p27	Preclinical	Prostate adenocarcinoma cell lines [152]	N/A	N/A
C1, C2, C3	SKP2	Sterically inhibits SKP2–Cks1–p27 interface	Preclinical	Metastatic melanoma cell lines, breast cancer cells [153]	N/A	N/A
SZL-P1-41 (Compound #25)	SKP2	Directly binds SKP2 to inhibit E3 activity	Preclinical	Prostate, lung, liver, and osteosarcoma tumor cell lines [154]	N/A	N/A
Longikaurin A	SKP2	Downregulates SKP2 expression	Preclinical	Hepatocellular carcinoma [155]	N/A	N/A
Curcumin	SKP2	Downregulates SKP2	Phase 3	Breast cancers [156], pancreatic cancer [157], glioma cells [158]	Prostate cancer, pancreatic cancer, colorectal cancer, MM, gastric cancer, breast cancer, leukemias and lymphomas, and more	[159,160]
Erioflorin	$\beta$-TrCP1	$\mathrm{Interferes}\mathrm{with}\beta$-TrCP1 to stabilize tumor suppressor Pdcd4	Preclinical	Kidney, breast, ovarian, and colon cancer cell lines [161]	N/A	N/A
GS143	$\beta$-TrCP1	$\mathrm{Inhibits}\beta$-TrCP1 ubiquitination of IkB, suppresses NF-kB signaling	Preclinical	N/A	N/A	N/A
Other RING E3 inhibitors
CCW 28-3	RNF4	Binds RNF4 to facilitate degradation of BRD4	Preclinical	Breast cancer cells [162]	N/A	N/A
GDC-0152	IAPs	SMAC mimetic, induces IAP degradation, activates caspases	Preclinical (Phase 1 terminated)	Breast cancer cell lines and xenografts [163]	Solid cancers	N/A
LCL161	IAPs	SMAC mimetic, induces degradation of cIAP-1	Phase 2	Various solid tumor cell lines [164], hepatocellular carcinoma [165], osteosarcoma [166], and more	Neoplasms, plasma cell myeloma, metastatic pancreatic cancer, myelofibrosis, small cell lung cancer, ovarian cancer, breast cancer, MM, and more	[167]
AT-406 (DEBIO1143, SM-406)	IAPs	SMAC mimetic; binds XIAP, cIAP-1, and cIAP-2; and activates caspases	Phase 3	Breast cancer [168], colorectal cancer [169], ovarian cancer [170]	Lymphoma, solid tumors, AML, NSCLC, squamous cell carcinoma of head and neck, MM, and more	[171,172]
AEG 35,156 (GEM640), AEG 40826	XIAP	Antisense oligonucleotides targeting XIAP mRNA to lower apoptotic threshold of cancer cells	Phase 2	Various cancer cell lines, xenograft models of colon, breast and osteosarcoma tumors [173]	Advanced solid tumors, leukemia, mammary carcinoma, pancreatic carcinoma, BCL, NSCLC, hepatocellular carcinoma, and more	[174]
TL 32711	IAPs	SMAC mimetic, induces degradation of cIAP-1, and caspase activation	Phase 2	MM cell lines and animal models [175]	Chronic myelomonocytic leukemia, relapsed epithelial ovarian cancer, myelodysplastic syndrome, peritoneal neoplasms, and more	[176]
YM155 (sepantronium bromide)	IAPs	Inhibits promoter of survivin gene (IAP protein)	Phase 2	Prostate cancer cell lines and xenografts [177]	Prostate cancer, melanoma, non-Hodgkin’s lymphoma, breast cancer, diffuse large-cell lymphoma, refractory B-cell lymphoma, and more	[178]
C25-140	TRAF6	Inhibits TRAF6–Ubc13 interaction specifically	Preclinical	Only studied in autoimmune and inflammatory disease models [179]	N/A	N/A
BC-1215	TRAF6 (via FBXO3 inhibition)	Antagonist of FBXO3, destabilizes TRAF6	Preclinical	Only studied in autoimmune and inflammatory disease models [180,181]	N/A	N/A
HECT E3 ligase inhibitors
HS-152	SMURF1	Reversibly blocks SMURF1-mediated RHOB ubiquitination	Preclinical	Inhibited protrusive RHOB-dependent activity in cell lines [182]	N/A	N/A
BI8622 and BI8626	HUWE1	Inhibit HUWE1 to stabilize assembly of Myc-repressive MIZ1 complex on Myc-activated target genes	Preclinical	Colorectal cancer [183], MM [184]	N/A	N/A
Compound 12	E6AP	Inhibits oncogenic E6–p53 interaction in E6–E6AP–p53 complex	Preclinical	HPV-positive cervical carcinoma cell lines [185]	N/A	N/A
Lutolein and CAF024	E6AP	Bind viral E6 to prevent hijacking of E6AP	Preclinical	HPV-positive cervical carcinoma cells [186]	N/A	N/A
Lig1, Lig2, Lig3	E6AP	Inhibit E6–E6AP interaction	Preclinical	N/A	N/A	N/A
N-acetyl phenylalanine	E6AP	Dissociates active E6AP trimer	Preclinical	N/A	N/A	N/A
CM11-1	E6AP	E6AP inhibitor, prevents polyubiquitination of Prx1 in E6-independent and -dependent manner	Preclinical	N/A	N/A	N/A
Heclin	HECT, non-specific	Induces conformational change in HECT domain to inhibit activity	Preclinical	N/A	N/A	N/A
RBR E3 ligase inhibitors
BAY 11-7082	LUBAC	Covalently binds active cysteine residues of E2′s Ubc13 and UbcH7 to prevent Ub conjugation	Preclinical	B-cell lymphoma, leukemia [187], gastric cancer [188]	N/A	N/A
gliotoxin	LUBAC	Selectively binds RBR domain of HOIP to inhibit Ub chain formation	Preclinical	N/A	N/A	N/A
HOIPIN-8	LUBAC	Inhibits LUBAC activity and suppresses NF-kB activation	Preclinical	ABC-DLBCL [189,190]	N/A	N/A
Bendamustine	LUBAC	Specifically inhibits HOIP	FDA approved (Phase 4)	Chronic lymphocytic leukemia, MM, non-Hodgkin’s lymphoma [191], and more	Ovarian cancer, MM, relapsed T-cell lymphoma, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, and more	[192,193,194,195]