PYZD-4409 is a novel small molecule inhibitor of Ubiquitin-activating enzyme UBA1/E1 enzyme with an IC50 of 20 uM (cell-free enzymatic assay).IC50 Value: 20 uM (cell-free enzymatic assay) [1]Target: E1 enzyme (Ubiquitin-activating enzyme)in vitro: PYZD-4409 inhibited the ATP-dependent activation of ubiquitin and subsequent transfer of the activated ubiquitin from the E1 to the common human E2 enzyme UBE2E2 in a gel-based assay. The IC50 of inhibition was estimated to be 20μM in a cell-free enzymatic assay. Suggesting specificity of PYZD-4409 for the E1 enzyme, the compound had no effect on unrelated enzymes such as α-Mannosidase II glycosylation enzyme or Luciferase at concentrations up to 100μM (data not shown). It also did not inhibit the summo E1, Uba2, at concentrations up to 100μM. In 5 of 8 leukemia and myeloma cell lines, PYZD-4409 induced cell death with a LD50 less than 10μM. Myeloma cell lines were particularly sensitive to E1 inhibition because PYZD-4409 induced cell death with 3 of 4 myeloma cell lines (ie, LP1, KMS11, and U226) having an LD50 of 3μM or less. In contrast, solid tumor cell lines were less sensitive with an LD50 of approximately 15 to 20μM [1]. in vivo: SCID mice were injected subcutaneously with MDAY-D2 murine leukemia cells and then treated with PYZD-4409 (10 mg/kg) or buffer control intraperitoneally daily on alternate days over 8 days. Sixteen days after tumor implantation, the mice were killed, and the tumors excised and weighed. Compared with control-treated mice, treatment with PYZD-4409 delayed tumor growth and decreased tumor weight without untoward toxicity. Inhibition of the E1 can achieve an antitumor effect in vivo [1].
DI-404 is a high-Affinity Peptidomimetic the DCN1-UBC12 Protein-Protein Interaction inhibitor (Kd= 6.9 nM). DI-404 effectively and selectively inhibits the neddylation of cullin 3 over other cullin members.
GS143 is a selective IκBα ubiquitination inhibitor with an IC50 of 5.2 μM for SCFβTrCP1-mediated IκBα ubiquitylation. GS143 suppresses NF-κB activation and transcription of target genes and does not inhibit proteasome activity. GS143 has anti-asthma effect[1][2].
UbcH5c-IN-1 (compound 6d) is a potent and selective small-molecule inhibitor of Ubiquitin-conjugating enzyme UbcH5c, with a Kd of 283 nM for E2 UbcH5c-IN-1 by covalent binding with Cys85. A promising lead compound for the development of new antirheumatoid arthritis (RA) agent[1].
CC-122 is a novel agent for DLBCL with antitumor and immunomodulatory activity.CC-122 binds CRBN and degrades Aiolos and Ikaros resulting in a mimicry of IFN signaling and apoptosis in DLBCL.In vitro: CC122 inhibits proliferation and induces apoptosis in ABC and GCB DLBCL. In DLBCL cell lines, CC122-induced degradation or short hairpin RNA-mediated knockdown of Aiolos and Ikaros correlates with increased transcription of interferon (IFN)-stimulated genes independent of IFN-α, -β, and -γ production and/or secretion and results in apoptosis in both activated B-cell (ABC) and germinal center B-cell DLBCL.[1]In vivo: Treatment of female CB-17 SCID mice with CC122 at 3 or 30 mg/kg once daily significantly decreased tumor growth in OCI-LY10 ABC-DLBCL (P = .028 and P < .001, respectively) and WSU-DLCL2 GCB-DLBCL derived xenograft models (P < .01) compared with the vehicle control. In a separate study, we assessed the ability of CC122 to promote degradation of Ikaros and Aiolos in vivo. In the 21-day efficacy study of WSU-DLCL2 xenograft transplanted mice, tumors were excised 1, 6, or 24 hours post final dosing. Aiolos and Ikaros expression was interrogated through immunohistochemistry (IHC) and was found to be decreased 64% and 30%, respectively, compared with vehicle within 1 hour of treatment, with a maximal reduction of 94% and 69%, respectively, observed at 6 hours. Aiolos and Ikaros levels partially recovered 24 hours postdosing with protein level within 20% and 34% of vehicle, respectively. The 24-hour postdose Aiolos and Ikaros expression represents the trough compound level following multiple doses of CC122. When the 1-hour time point is compared with the 24-hour postdose time point, there is a significant reduction in Aiolos but not Ikaros expression; however, at the 6-hour time point, both transcription factors are significantly different from the 24-hour time point. Taken together, these data reveal that CC122 inhibited DLBCL tumor growth in vivo and that this activity was associated with the degradation of Aiolos and Ikaros in both ABC- and GCB-DLBCL xenograft models.[1]"Mice[1]Female SCID mice (CB17/Icr-Prkdcscid, Charles River) were 8 weeks old, with body weights ranging from 15.0 to 23.2 g, on day 1 of these studies. Each SCID mouse was injected subcutaneously in the right flank with 5x106 OCI-LY10 cells (0.2 ml cell suspension). Tumors were calipered in two dimensions to monitor growth as their mean volume approached 100–150 mm3. Fourteen days (WSU-DLCL2) or twenty-one days (OCI-LY10) after tumor cell implantation, mice were sorted into treatment groups (n=10/group). Tumors were callipered twice weekly during the study. CC122 was suspended in 0.5% carboxymethyl cellulose: 0.25% Tween-80 in de-ionized water. Vehicle and CC122 were each administered via oral gavage (p.o.) once daily for twenty-eight days (qd x28). [1]
Rugonersen (RG6091; RO7248824) is a locked-nucleic acid (LNA)- modified antisense oligonucleotides (ASOs), and results in reduction of ubiquitin-protein ligase E3A (UBE3A) silencing. Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of neuronal E3 ligase UBE3A, Rugonersen has been used for AS reasearch[1][2].
(Rac)-Nutlin-3 (Rebemadlin), an active enantiomer of Nutlin-3, is a potent murine double minute (MDM2) inhibitor (IC50=90 nM). (Rac)-Nutlin-3 inhibits MDM2-p53 interactions and stabilizes the p53 protein, and induces cell autophagy and apoptosis. (Rac)-Nutlin-3 has the potential for the study of TP53 wild-type ovarian carcinomas[1][2].
TD-106 is a cereblon (CRBN) modulator, which can be used for targeted protein degradation. BRD4 PROTACs with TD-106 induce BRD4 degradation[1].
TZ9 is a novel inhibitor of Rad6 ubiquitin conjugating enzyme(E2 enzyme); inhibits MDA-MB-231 cell proliferation with IC50 of ~6 uM.IC50 value: 6 uM [1]Target: Rad6 inhibitorThe bulk of MDA-MB-231 cells treated with 10 μmol/L or more SMI #9 displayed a round morphology compared with controls and less than 5 μmol/L doses of SMI #9. Simultaneous comparison of SMIs #8 and 9 confirmed SMI #9 inhibits Matrigel-induced migration of MDA-MB-231 cells in a dose-dependent manner compared with SMI #8. 5 μmol/L SMI #9 treatment triggered morphologic changes consistent with apoptosis in a time-dependent manner. 5 μmol/L SMI #9 treatment of MDA-MB-231 cells for 24 hours increased the proportion of G2–M-arrested cells by 2-fold and was accompanied by a proportional decrease in S-phase cells. SMIs #8 or 9 treatments dramatically reduced β-catenin staining as visualized by reduced merged Rad6/β-catenin yellow fluorescence.
PRT4165 is a potent inhibitor of PRC1-mediated H2A ubiquitylation.
VII-31 is a potent NEDDylation pathway activator to inhibit the tumor progression in vitro and in vivo. VII-31 induces apoptosis via intrinsic and extrinsic pathways[1].
HB007 is a small ubiquitin-related modifier 1 (SUMO1) degrader. HB007 induces ubiquitination and degradation of SUMO1, resulting in reduced tumor growth in vivo. HB007 can be used for the research of brain, breast, colon, and lung cancers[1][2].
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[1][2].
Cbl-b-IN-13 (Example 520) is a Cbl-b inhibitor with an IC50 of <100 nM. Cbl-b-IN-13 has the ability to activate T-cells[1].
DI-591 (DI591) is a potent, selective, cell-permeable inhibitor of the DCN1-UBC12 interaction with Ki of 10-12 nM for human DCN1 and DCN2; displays no affinity against DCN3/4/5 (Ki>10 uM); selectively inhibits neddylation of cullin 3 but has no or minimal effect on neddylation of other cullin family members; accumulates NRF2 protein and its transcriptional activation in cells.
Smurf1-IN-1 is an orally active and selective inhibitor of specific E3 ubiquitin protein ligase 1 (SMURF1) with an IC50 of 92 nM. Smurf1-IN-1 has significant efficacy in rats model of pulmonary hypertension[1].
Teslexivir (BTA074) hydrochloride is a potent antiviral agent. Teslexivir hydrochloride is a potent and selective inhibitor of the interaction between two essential viral proteins, E1 and E2, an association that is a necessary step in the DNA replication and thus viral production for Human Papilloma Virus (HPV) 6 and 11. Teslexivir hydrochloride can be used for condyloma research[1].
BI8622 is a specific inhibitor of the ubiquitin ligase HUWE1 with an IC50 of 3.1 μM[1].
Skp2 inhibitor 2 (14f) is an inhibitor of F-box protein S-phase kinase-associated protein 2 (Skp2), with an IC50 value of 10.2 μM (Skp2-Cks1). Skp2 is a part of cullin-RING ligases, which recruits and ubiquitinates substrates, involving in proteolytic and non-proteolytic process[1].
TAK-243 is a potent and selective ubiquitin-like modifier activating enzyme 1 (UBA1) inhibitor.
COH000 is an inhibitor of Ubiquitin-like 1-activating enzyme (SUMO-activating enzyme), with an IC50 of 0.2 μM for SUMOylation in vitro[1].
Cbl-b-IN-1 (example 519) is a Cbl-b inhibitor, extracted from patent WO2019148005A1, with an IC50 <100 nM[1].
WS-383 (WS383) is a highly potent, selective, and cellular active inhibitor of DCN1-UBC12 interaction with IC50 of 11 nM; inhibits Cul3/1 neddylation selectively over other cullins and also induces accumulation of p21, p27 and NRF2; exhibits cellular target engagement to DCN1 in MGC-803 cells, enhances the thermal stability of cellular DCN1 protein even at 1 uM
Cbl-b-IN-5 (compound 6) is a Cbl-b inhibitor (IC50=3-10 µM). Cbl-b-IN-5 has the potential to be used in the study of cancer and related diseases amenable to immune system modulation[1].
EN450 is a cysteine-reactive covalent molecular glue degrader targeting NF-κB. EN450 interacts with allosteric C111 in the E2 ubiquitin ligase UBE2D. EN450 induces the ternary complex formation between UBE2D and NFKB1. EN450 exerts its anti-proliferative effects through a Cullin E3 ligase and proteasome-dependent mechanism[1].
Ginkgolic Acid is a natural compound with suspected cytotoxic, allergenic, mutagenic and carcinogenic properties, and it can inhibit protein SUMOylation both in vitro and in vivo without affecting in vivo ubiquitination.
Cbl-b-IN-3 (Compound 23) is a casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) inhibitor with an IC50 of < 1 nM. Cbl-b is an E3 ubiquitin ligase that negatively regulates T-cell activation[1].
Homo-PROTAC cereblon degrader 1 (compound 15a) is a highly potent and efficient cereblon (CRBN) degrader with only minimal effects on IKZF1 and IKZF3[1].
DCN1-UBC12-IN-3 is potent and selective DCN1-UBC12 inhibitor with an IC50 of 2.25 nM. Anticardiac fibrotic effect[1].
Antitumor agent-81 (compound 5a) is a low cytotoxic P62-RNF168 agonist that promotes the interaction of P62 with RNF168. Antitumor agent-81 induces a decrease in RNF168-mediated H2A ubiquitination and impairs homologous recombination-mediated DNA repair. Antitumor agent-81 also inhibits mice xenograft tumor growth in a dose-dependent manner[1].