Description
NSC-69723 (343351-67-7) is a selective inhibitor of the E2 ubiquitin-conjugating enzyme, Ubc13-Uev1A. Does not inhibit UbcH5c activity. Impedes the formation of the Ubc13 and inhibits NF-κB activation in activated B cell-like diffuse large B-cell lymphoma (ABC-DLBCL) cells.1Blocks proliferation and survival of both ABC-DLBCL and germinal center B cell-like (GCB)-DLBCL cell lines, and survival of primary DLBCL cells. NSC-69723 acts via covalent bonding to E2 active site thiol.2,3Induces neuroblastoma cell death via activation of p53 and JNK.4
Uses
NSC 697923 is a cell-permeable and selective inhibitor of the ubiquitin-conjugating (E2) enzyme Ubc13-Uev1A and exhibits potent cytotoxicity in a panel of Neuroblastoma (NB) cell lines. NSC 697923 also inhibits the proliferation and survival of diffuse large B-cell lymphoma cells (DLBCL).
in vivo
NSC697923 (5mg/kg; i.p.; daily for 10 days) suppresses NB tumor growth in SH-SY5Y and NGP xenografts[1].
| Animal Model: | 5- to 6-week-old female athymic Ncr nude mice (orthotopic mouse model of NB; SH-SY5Y and NGP xenografts)[1] |
| Dosage: | 5mg/kg |
| Administration: | I.p.; daily for 10 days |
| Result: | Significant tumor regression in both SH-SY5Y and NGP xenografts.
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Background
NSC-697923 is a small-molecule inhibitor of the E2 ubiquitin-conjugating enzyme Ubc13-Uev1A. NSC-697923 blocked formation of Ubc13 and ubiquitin thioester conjugates, and suppressed constitutive NF-κB activity in diffuse large B cell lymphoma cells. Inhibition of ubiquitin-dependent DNA damage signaling was observed, but not formation of the phosphorylated form of histone variant H2AX, which is consistent with NSC-697923 targeting of nuclear Ubc13. Additional data suggested that NSC-697923 interacted with the Ubc13 active site cysteine. UBE2N is an E2 ubiquitin-conjugating enzyme that catalyzes K63-linked poly-Ub chain formation. UBE2N forms a heterodimer with MMS2 or Uev1A to exert its E2 ligase function. NSC-697923 treatment of neuroblastoma cells increased apoptosis and nuclear p53 accumulation, and enhanced tumor suppression. NSC-697923 also inhibited caspase-1 enzymatic activity and NLRP3 protein expression by suppressing the NF-κB signaling pathway. NSC-697923 inhibited joint swelling and NLRP3 inflammasome activation in an animal model of gouty arthritis.
References
[1] MARY PULVINO. Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A.[J]. Blood, 2012, 120 8: 1668-1677. DOI:
10.1182/blood-2012-02-406074[2] SAM STRICKSON. The anti-inflammatory drug BAY 11-7082 suppresses the MyD88-dependent signalling network by targeting the ubiquitin system.[J]. Biochemical Journal, 2013, 451 3: 427-437. DOI:
10.1042/bj20121651[3] CURTIS D. HODGE. Covalent Inhibition of Ubc13 Affects Ubiquitin Signaling and Reveals Active Site Elements Important for Targeting[J]. ACS Chemical Biology, 2015, 10 7: 1718-1728. DOI:
10.1021/acschembio.5b00222[4] J CHENG. A small-molecule inhibitor of UBE2N induces neuroblastoma cell death via activation of p53 and JNK pathways[J]. Cell Death & Disease, 2014, 5 2: e1079-e1079. DOI:
10.1038/cddis.2014.54
