| Abstract: |
Chemical control of cullin neddylation is attracting increased attention based largely on the successes of the NEDD8-activating enzyme (E1) inhibitor pevonedistat. Recently reported chemical probes enable selective and time-dependent inhibition of downstream members of the neddylation trienzymatic cascade including the co-E3, DCN1. In this work, we report the optimization of a novel class of small molecule inhibitors of the DCN1-UBE2M interaction. Rational X-ray co-structure enabled optimization afforded a 25-fold improvement in potency relative to the initial screening hit. The potency gains are largely attributed to additional hydrophobic interactions mimicking the N-terminal acetyl group that drives binding of UBE2M to DCN1. The compounds inhibit the protein-protein interaction, block NEDD8 transfer in biochemical assays, engage DCN1 in cells, and selectively reduce the steady-state neddylation of Cul1 and Cul3 in two squamous carcinoma cell lines harboring DCN1 amplification. © 2019 American Chemical Society. |
| Keywords: |
controlled study; protein expression; unclassified drug; nonhuman; animal cell; steady state; protein protein interaction; protein; protein binding; drug synthesis; structure activity relation; cyclopropane derivative; pyrazole derivative; protein p27; immunoblotting; reactive oxygen metabolite; hydrogen bond; alkylation; pharmacophore; catalysis; protein p21; molecular weight; thin layer chromatography; thermostability; physical chemistry; cyclin e; proton nuclear magnetic resonance; trans isomer; cullin; diastereoisomer; drug solubility; hydrophobicity; neddylation; biochemical analysis; transcription factor nrf2; drug mixture; ligase inhibitor; pyridone derivative; microsome; nedd8 protein; article; metabolic stability; heteronuclear multiple bond correlation; ube2m protein; hcc95 cell line; pevonedistat; 3 methyl n [(3 methyl 6 oxo 1 phenyl 4 (4 tolyl) 4,5,6,7 tetrahydro 1h pyrazolo[3,4 b]pyridin 5 yl]benzamide; 4 (4 fluorobenzylidene) 2 (3 tolyl)oxazol 5(4h) one; defective in cullin neddylation 1; n [4 (4 fluorophenyl) 3 methyl 6 oxo 1 phenyl 4,5,6,7 tetrahydro 1h pyrazolo[3,4 b]pyridin 5 yl] 3 methylbenzamide; n [7 ethyl 4 (4 fluorophenyl) 3 methyl 6 oxo 1 phenyl 4,5,6,7 tetrahydro 1h pyrazolo[3,4 b]pyridin 5 yl] 3 methylbenzamide; cal-33 cell line
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