| Literature DB >> 29547696 |
Jared T Hammill1, Daniel C Scott2,3, Jaeki Min1, Michele C Connelly1, Gloria Holbrook1, Fangyi Zhu1, Amy Matheny1, Lei Yang1, Bhuvanesh Singh4, Brenda A Schulman2,3, R Kiplin Guy1.
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. Ultimately, we anticipate that these studies will identify early lead compounds for clinical development for the treatment of lung squamous cell carcinomas and other cancers.Entities:
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Year: 2018 PMID： 29547696 PMCID： PMC5898815 DOI： 10.1021/acs.jmedchem.7b01277
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446