We previously reported the discovery, validation, and structure-activity relationships of a series of piperidinyl ureas that potently inhibit the DCN1-UBE2M interaction. We demonstrated that compound 7 inhibits both the DCN1-UBE2M protein-protein interaction and DCN1-mediated cullin neddylation in biochemical assays and reduces levels of steady-state cullin neddylation in a squamous carcinoma cell line harboring DCN1 amplification. Although compound 7 exhibits good solubility and permeability, it is rapidly metabolized in microsomal models (CL int = 170 mL/min/kg). This work lays out the discovery of an orally bioavailable analogue, NAcM-OPT (67). Compound 67 retains the favorable biochemical and cellular activity of compound 7 but is significantly more stable both in vitro and in vivo. Compound 67 is orally bioavailable, well tolerated in mice, and currently used to study the effects of acute pharmacologic inhibition of the DCN1-UBE2M interaction on the NEDD8/CUL pathway.
|Number of pages||13|
|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, and Veterinary pathology cores of St. Jude Children’s Research Hospital for use of their personnel and facilities. 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