TY - JOUR
T1 - Discovery of Novel Pyrazolo-pyridone DCN1 Inhibitors Controlling Cullin Neddylation
AU - Kim, Ho Shin
AU - Hammill, Jared T.
AU - Scott, Daniel C.
AU - Chen, Yizhe
AU - Min, Jaeki
AU - Rector, Jonah
AU - Singh, Bhuvanesh
AU - Schulman, Brenda A.
AU - Guy, R. Kiplin
N1 - Publisher Copyright:
© 2019 American Chemical Society.
PY - 2019/9/26
Y1 - 2019/9/26
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.9b00410
DO - 10.1021/acs.jmedchem.9b00410
M3 - Article
C2 - 31465221
AN - SCOPUS:85072687229
SN - 0022-2623
VL - 62
SP - 8429
EP - 8442
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 18
ER -