E1/E2/E3 Enzyme Inhibitor

TAK-243 (MLN7243) is a first-in-class, selective ubiquitin activating enzyme, UAE (UBA1) inhibitor (IC₅₀=1 nM), which blocks ubiquitin conjugation, disrupting monoubiquitin signaling as well as global protein ubiquitination. TAK-243 (MLN7243) induces endoplasmic reticulum (ER) stress, abrogates NF-κB pathway activation and promotes apoptosis.

Nutlin-3a (Rebemadlin), an active enantiomer of Nutlin-3, is a potent murine double minute (MDM2) inhibitor (IC₅₀=90 nM). Nutlin-3a inhibits MDM2-p53 interactions and stabilizes the p53 protein, and induces cell autophagy and apoptosis. Nutlin-3a has the potential for the study of TP53 wild-type ovarian carcinomas.

Subasumstat (TAK-981) is a first in class and selective inhibitor of the SUMOylation enzymatic cascade, with potential immune-activating and antineoplastic activities.

Nutlin-3 is a commercial available p53-MDM2 inhibitor, with K_i of 90 nM.

Pentagalloylglucose (Penta-O-galloyl-β-D-glucose) is an orally active gallic tannin compound and an inducer of apoptosis and autophagy. Pentagalloglucose induces cell apoptosis and autophagy through the GSK3β/β-catenin pathway. Pentagalloylglucose inhibits UBE2T-mediated p53 ubiquitination, upregulates p53, downregulates RRM1/RRM2 in pancreatic cancer organoids. Pentagalloglucose has antioxidant, anti mutagenic, anti-inflammatory, anticonvulsant, cardioprotective, anti allergic, cholesterol lowering, and anti-tumor activities.

M435-1279 is a UBE2T inhibitor. M435-1279 inhibits the Wnt/β-catenin signaling pathway hyperactivation through blocking UBE2T-mediated degradation of RACK1.

HB007 is a SUMO1 molecular glue degrader targeting CAPRIN1 and FBXO42. HB007 selectively binds CAPRIN1 to induce CAPRIN1-FBXO42 interaction, recruits SUMO1 to the CAPRIN1-CUL1-FBXO42 E3 ligase complex, and drives SUMO1 ubiquitination and degradation without affecting SUMO2/3. HB007 induces TCF4 deSUMOylation and proteasomal degradation to inhibit StarD7 transcriptional activity, reduces StarD7 mRNA and protein levels, and triggers ER stress and ROS production. HB007 can be used for the research of brain cancer, breast cancer, colon cancer, lung cancer.

Mezigdomide (CC-92480), a cereblon E3 ubiquitin ligase modulating agent (CELMoD), acts as a molecular glue. Mezigdomide shows high affinity to cereblon, resulting in potent antimyeloma activity.

Idasanutlin (RG7388) is an orally bioavailable MDM2 inhibitor with an IC₅₀ of 6 nM. Idasanutlin disrupts MDM2-p53 binding, stabilizes and activates p53, triggering cell cycle arrest, apoptosis, and reduced cancer cell viability. Idasanutlin reduces EGFR protein expression and phosphorylation, suppresses downstream SHP2, MEK1/2, ERK1/2, AKT, mTOR, p70(S6K1), and S6 signaling. Idasanutlin induces mitochondrial ROS production, drives p38 MAPK phosphorylation, upregulates NOXA, and mediates caspase-3-dependent apoptosis and gasdermin E-mediated pyroptosis. Idasanutlin can be used for the research of TP53-mutant non-small cell lung cancer, T-cell acute lymphoblastic leukemia, colorectal carcinoma, melanoma, diffuse large B-cell lymphoma, mantle cell lymphoma, non-Hodgkin lymphoma, severe fever with thrombocytopenia syndrome, neuroblastoma, acute lymphoblastic leukemia, relapsed or refractory acute myeloid leukemia, osteosarcoma, solid tumors, and hematological tumors.

ML-792 is a potent and selective inhibitor of SAE/SUMO1 and SAE/SUMO2 in enzymatic assays (IC₅₀ values of 3 and 11 nM, respectively) compared with NAE/NEDD8 and UAE/ubiquitin (IC₅₀> values of 32 μM and >100 μM, respectively).

2-D08 is a cell permeable, mechanistically unique inhibitor of protein SUMOylation. 2-D08 also inhibits Axl with an IC₅₀ of 0.49 nM.

Navtemadlin (AMG 232) is a potent, selective and orally available inhibitor of p53-MDM2 interaction, with an IC₅₀ of 0.6 nM. Navtemadlin binds to MDM2 with a K_d of 0.045 nM.

PYR-41 is a selective and cell permeable inhibitor of ubiquitin-activating enzyme E1 with an IC₅₀ of < 10 μM, with little activity at E2 and E3.

Indole-3-carbinol (I3C) inhibits NF-κB activity and also is an Aryl hydrocarbon receptor (AhR) agonist, and an inhibitor of WWP1 (WW domain-containing ubiquitin E3 ligase 1).

NX-1607 (Compound 23) is an inhibitor of Cbl-b, an E3 enzyme in the ubiquitin-proteasome pathway, with an IC₅₀ value of less than 1 nM. NX-1607 can be used in cancer research.

PRT4165 is a potent inhibitor of polycomb-repressive complex 1 (PRC1)-mediated H2A ubiquitylation.

Heclin is a HECT E3 ubiquitin ligases inhibitor. Heclin inhibits Smurf2, Nedd4, WWP1 (IC₅₀ values are 6.8, 6.3, 6.9 μM) and can be used for the research of gastric cancer.

RB-3, a polycomb repressive complex 1 (PRC1) inhibitor, binds to RING1B-BMI1f, with a K_d of 2.8 μM.

Ginkgolic Acid is a natural compound that inhibits SUMOylation with an IC₅₀ of 3.0 μM in in vitro assay.

NSC697923 is a potent UBE2N (ubiquitin-conjugating enzyme E2 N, Ubc13) inhibitor. NSC697923 induces neuroblastoma (NB) cell death via promoting nuclear importation of p53 in p53 wild-type NB cells. NSC697923 also induces cell death in p53 mutant NB cells by activation of JNK-mediated apoptotic pathway. NSC697923 inhibits DNA damage and NF-κB signaling. Antitumor activity.