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.
|Number of pages||14|
|Journal||Journal of Medicinal Chemistry|
|State||Published - Apr 12 2018|
Bibliographical noteFunding Information:
We acknowledge the High Throughput Biosciences Center, Medicinal Chemistry Center, Compound Management, and High Throughput Analytical Chemistry Centers in Chemical Biology and Therapeutics, Hartwell Center, for use of their personnel and facilities. We thank the staff at the BL8.2.1 and 22-ID beamlines at the Advanced Light Source and Advanced Photon Source. This study was funded through B.A.S., HHMI, and NIH R37GM069530, P30CA021765; J.T.H., NIH F32GM113310; American Syrian Lebanese Associated Charities, and St Jude Children’s Research Hospital.
© 2018 American Chemical Society.
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery