TY - JOUR
T1 - Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation
AU - Hammill, Jared T.
AU - Bhasin, Deepak
AU - Scott, Daniel C.
AU - Min, Jaeki
AU - Chen, Yizhe
AU - Lu, Yan
AU - Yang, Lei
AU - Kim, Ho Shin
AU - Connelly, Michele C.
AU - Hammill, Courtney
AU - Holbrook, Gloria
AU - Jeffries, Cynthia
AU - Singh, Bhuvanesh
AU - Schulman, Brenda A.
AU - Guy, R. Kiplin
N1 - Publisher Copyright:
© 2018 American Chemical Society.
PY - 2018/4/12
Y1 - 2018/4/12
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.7b01282
DO - 10.1021/acs.jmedchem.7b01282
M3 - Article
C2 - 29547693
AN - SCOPUS:85045569727
SN - 0022-2623
VL - 61
SP - 2694
EP - 2706
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -