Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

Hammill, Jared T.; Scott, Daniel C.; Min, Jaeki; Connelly, Michele C.; Holbrook, Gloria; Zhu, Fangyi; Matheny, Amy; Yang, Lei; Singh, Bhuvanesh; Schulman, Brenda A.; Guy, R. Kiplin

doi:10.1021/acs.jmedchem.7b01277

Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

Journal Article · Fri Mar 16 00:00:00 EDT 2018 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/acs.jmedchem.7b01277· OSTI ID:1434738

Hammill, Jared T. ^[1]; Scott, Daniel C. ^[2]; Min, Jaeki ^[2]; Connelly, Michele C. ^[2]; Holbrook, Gloria ^[2]; Zhu, Fangyi ^[2]; Matheny, Amy ^[2]; Yang, Lei ^[2]; Singh, Bhuvanesh ^[3]; Schulman, Brenda A. ^[2]; ^[1]

St. Jude Children’s Research Hospital, Memphis, TN (United States); Univ. of Kentucky, Lexington, KY (United States)
St. Jude Children’s Research Hospital, Memphis, TN (United States)
Memorial Sloan Kettering Cancer Center, New York, NY (United States)

We previously discovered and validated a class of piperidinyl ureas that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation of cullins. Here, we report preliminary structure–activity relationship studies aimed at advancing our high-throughput screen hit into a tractable tool compound for dissecting the effects of acute DCN1–UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled optimization led to a 100-fold increase in biochemical potency and modestly increased solubility and permeability as compared to our initial hit. The optimized compounds inhibit the DCN1–UBE2M protein–protein interaction in our TR-FRET binding assay and inhibit cullin neddylation in our pulse-chase NEDD8 transfer assay. The optimized compounds bind to DCN1 and selectively reduce steady-state levels of neddylated CUL1 and CUL3 in a squamous cell carcinoma cell line. Furthermore, we anticipate that these studies will identify early lead compounds for clinical development for the treatment of lung squamous cell carcinomas and other cancers.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: NIH

OSTI ID:: 1434738

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 7 Vol. 61; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

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