E1/E2/E3 Enzyme

Pevonedistat (MLN4924) is a potent and selective NEDD8 activating enzyme (NAE) inhibitor (IC50=4.7 nM) with therapeutic potential for myelodysplastic syndromes (MDS) and antitumor activity.

Indole-3-carbinol (I3C), a naturally occurring, orally available cleavage product of the glucosinolate glucobrassicanin, inhibits NF-κB and IκBα kinase activation.

ML-792 is a specific small ubiquitin-like modifier activating enzyme (SUMO) inhibitor. ML-792 selectively inhibits SAE SUMO1 and SAE SUMO2 with IC50 of 3 and 11 nM.

TAK-243 (MLN7243) is a selective inhibitor of the ubiquitin-activating enzyme UAE (IC50=1 nM), blocking ubiquitin binding and disrupting both mono-ubiquitin signaling and overall protein ubiquitination. TAK-243 exhibits antitumor activity and promotes apoptosis.

2-D08 is a synthetic flavone that inhibits sumoylation, also inhibits Axl with an IC50 of 0.49 nM.2-D08 showed anti-aggregatory and neuroprotective effect.

Nutlin-3a is the active enantiomer of Nutlin-3, an MDM2 antagonist that inhibits MDM2-p53 interaction (Ki=90 nM) and activates p53. Nutlin-3a binds preferentially to the p53-binding pocket of MDM2, leading to stabilization of p53 and activation of the p53 pathway. Nutlin-3a has antitumor activity.

Skp2 inhibitor 2 (14f) impedes the F-box protein S-phase kinase-associated protein 2 (Skp2), demonstrating an IC50 of 10.2 μM against Skp2-Cks1. This compound targets Skp2, a component of cullin-RING ligases that recruits and ubiquitinates substrates, playing roles in both proteolytic and non-proteolytic processes [1].

TRAF6 peptide TFA, a specific inhibitor of the TRAF6-p62 interaction, significantly inhibits NGF-dependent ubiquitination of TrkA. This peptide demonstrates promising research applications in various neurological disorders, including Alzheimer's disease (AD), Parkinson's, ALS, head trauma, epilepsy, and stroke [1].

Smurf1-IN-1, a selective E3 ubiquitin protein ligase 1 (SMURF1) inhibitor, exhibits oral activity with an IC50 of 92 nM and demonstrates considerable efficacy in a rat model of pulmonary hypertension [1].

Cbl-b-IN-6 (Compound 246) is an inhibitor of casitas B-lineage lymphoma-b (Cbl-b) and c-Cbl, with half-maximal inhibitory concentrations (IC50s) of 6.7 nM for Cbl-b and 5.2 nM for c-Cbl, respectively [1].

Cbl-b-IN-7 (Compound 248) is an inhibitor of casitas B-lineage lymphoma-b (Cbl-b) and c-Cbl, with half-maximal inhibitory concentrations (IC50s) of 6.7 nM and 5.2 nM, respectively [1].

Cbl-b-IN-8 (Compound 293) is an inhibitor of casitas B-lineage lymphoma-b (Cbl-b) and c-Cbl, with half maximal inhibitory concentrations (IC50s) of 5.5 nM and 7.8 nM, respectively [1].

Cbl-b-IN-9 (Compound 300) is a potent inhibitor targeting casitas B-lineage lymphoma-b (Cbl-b) and c-Cbl, with half-maximal inhibitory concentrations (IC50s) of 5.6 nM and 4.7 nM, respectively [1].

Cbl-b-IN-10 (Compound 463) is a potent inhibitor of both casitas B-lineage lymphoma-b (Cbl-b) and c-Cbl, with half-maximal inhibitory concentrations (IC50s) of 6.0 nM and 3.5 nM, respectively [1].

Cbl-b-IN-11 (Compound 466) is an inhibitor of casitas B-lineage lymphoma-b (Cbl-b) and c-Cbl, with half-maximal inhibitory concentrations (IC50s) of 6.4 nM and 6.1 nM, respectively [1].

Cbl-b-IN-12 (Example 10) is a CBL-B inhibitor with an IC50 of less than 100 nM [1].

Cbl-b-IN-13 (Example 520) is a potent Cbl-b inhibitor with an IC50 of less than 100 nM, capable of activating T-cells [1].

RNF5 agonist 1 (analog-1), a structural analog of the RNF5 inhibitor inh-02, is a potent RNF5 agonist. In CFBE41o- cells expressing F508del-CFTR, RNF5 agonist 1 enhances the ubiquitination of ATG4B.

HGC652 is a molecular glue that targets the E3 ubiquitin ligase TRIM21, facilitating the formation of a ternary complex between TRIM21 and NUP98, which induces the degradation of NUP155 and nuclear pore complex proteins, ultimately leading to cell death. HGC652 inhibits the proliferation of various cancer cells, with its antiproliferative activity depending on the expression level of TRIM21.

Ethanolamine-Thalidomide-4-OH is an E3 ligase ligand-linker conjugate used in the synthesis of PROTACs, such as [PROTAC BTK Degrader-13].

PRC1-IN-1 (compound RB-4) is an inhibitor of the polycomb repressive complex 1 (PRC1) with an IC50 of 2.3 μM. It targets RING1B-BMI1, RING1A-BMI1, and RING1B-PCGF1, exhibiting IC50 values of 2.8 μM, 2.6 μM, and 1.8 μM, respectively.

Mezigdomide (CC-92480) is a potent, novel, selective and active cereblon E3 ubiquitin ligase modulator (CELMoD) that acts as a molecular glue. Mezigdomide has anti-myeloma activity. [1]

Cbl-b-IN-3 is a potent inhibitor of casitas b lineage lymphoma proto-oncogene-b (Cbl-b) (ic50 < 1 nM).

MI-773 (SAR405838 (MI 773)) is an orally available MDM2 antagonist with Ki of 0.88 nM. Phase 1.