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

Abstract

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.

Authors:
 [1];  [2];  [2];  [2];  [2];  [2];  [2];  [2];  [3];  [2]; ORCiD logo [1]
  1. St. Jude Children’s Research Hospital, Memphis, TN (United States); Univ. of Kentucky, Lexington, KY (United States)
  2. St. Jude Children’s Research Hospital, Memphis, TN (United States)
  3. Memorial Sloan Kettering Cancer Center, New York, NY (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Institutes of Health (NIH)
OSTI Identifier:
1434738
Grant/Contract Number:  
R37GM069530; P30CA021765; F32GM113310
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 61; Journal Issue: 7; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Substituents; Optimization; Inhibitors; Inhibition; Urea

Citation Formats

Hammill, Jared T., Scott, Daniel C., Min, Jaeki, Connelly, Michele C., Holbrook, Gloria, Zhu, Fangyi, Matheny, Amy, Yang, Lei, Singh, Bhuvanesh, Schulman, Brenda A., and Guy, R. Kiplin. Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation. United States: N. p., 2018. Web. doi:10.1021/acs.jmedchem.7b01277.
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. Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation. United States. doi:10.1021/acs.jmedchem.7b01277.
Hammill, Jared T., Scott, Daniel C., Min, Jaeki, Connelly, Michele C., Holbrook, Gloria, Zhu, Fangyi, Matheny, Amy, Yang, Lei, Singh, Bhuvanesh, Schulman, Brenda A., and Guy, R. Kiplin. Fri . "Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation". United States. doi:10.1021/acs.jmedchem.7b01277. https://www.osti.gov/servlets/purl/1434738.
@article{osti_1434738,
title = {Piperidinyl Ureas Chemically Control Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation},
author = {Hammill, Jared T. and Scott, Daniel C. and Min, Jaeki and Connelly, Michele C. and Holbrook, Gloria and Zhu, Fangyi and Matheny, Amy and Yang, Lei and Singh, Bhuvanesh and Schulman, Brenda A. and Guy, R. Kiplin},
abstractNote = {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.},
doi = {10.1021/acs.jmedchem.7b01277},
journal = {Journal of Medicinal Chemistry},
issn = {0022-2623},
number = 7,
volume = 61,
place = {United States},
year = {2018},
month = {3}
}

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Cited by: 9 works
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