期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 7, 页码 2680-2693出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01277
关键词
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资金
- HHMI
- NIH [R37GM069530, P30CA021765, F32GM113310]
- American Syrian Lebanese Associated Charities
- St Jude Children's Research Hospital
- NATIONAL CANCER INSTITUTE [P30CA021765] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [F32GM113310, R37GM069530] Funding Source: NIH RePORTER
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.
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