2. Academic Validation
  3. Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation

  • J Med Chem. 2018 Apr 12;61(7):2694-2706. doi: 10.1021/acs.jmedchem.7b01282.
Jared T Hammill 1,  Deepak Bhasin 1,  Daniel C Scott 2 3,  Jaeki Min 1,  Yizhe Chen 1,  Yan Lu 1,  Lei Yang 1,  Ho Shin Kim 1,  Michele C Connelly 1,  Courtney Hammill 1,  Gloria Holbrook 1,  Cynthia Jeffries 1,  Bhuvanesh Singh 4,  Brenda A Schulman 2 3,  R Kiplin Guy 1
Affiliations

Affiliations

  • 1 Department of Chemical Biology and Theraputics , St. Jude Children's Research Hospital , Memphis , Tennessee 38105 United States.
  • 2 Howard Hughes Medical Institute , St. Jude Children's Research Hospital , Memphis , Tennessee 38105 United States.
  • 3 Department of Structural Biology , St. Jude Children's Research Hospital , Memphis , Tennessee 38105 United States.
  • 4 Department of Surgery, Laboratory of Epithelial Cancer Biology , Memorial Sloan Kettering Cancer Center , New York , New York , 10065 United States.
PMID: 29547693 DOI: 10.1021/acs.jmedchem.7b01282
Abstract

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 (CLint = 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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