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

Jared T. Hammill; Deepak Bhasin; Daniel C. Scott; Jaeki Min; Yizhe Chen; Yan Lu; Lei Yang; Ho Shin Kim; Michele C. Connelly; Courtney Hammill; Gloria Holbrook; Cynthia Jeffries; Bhuvanesh Singh; Brenda A. Schulman; R. Kiplin Guy

doi:10.1021/acs.jmedchem.7b01282

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

Jared T. Hammill
, Deepak Bhasin
, Daniel C. Scott
, Jaeki Min
, Yizhe Chen
, Yan Lu
, Lei Yang
, Ho Shin Kim
, Michele C. Connelly
, Courtney Hammill
, Gloria Holbrook
, Cynthia Jeffries
, Bhuvanesh Singh
, Brenda A. Schulman
, R. Kiplin Guy

Producción científica: Article › revisión exhaustiva

59 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	2694-2706
Número de páginas	13
Publicación	Journal of Medicinal Chemistry
Volumen	61
N.º	7
DOI	https://doi.org/10.1021/acs.jmedchem.7b01282
Estado	Published - abr 12 2018

Nota bibliográfica

Publisher Copyright:
© 2018 American Chemical Society.

Financiación

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.

Financiadores	Número del financiador
St Jude Children’s Research Hospital
National Institutes of Health (NIH)	P30CA021765, R37GM069530
Howard Hughes Medical Institute
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	F32GM113310
American Lebanese Syrian Associated Charities

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.7b01282

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Hammill, J. T., Bhasin, D., Scott, D. C., Min, J., Chen, Y., Lu, Y., Yang, L., Kim, H. S., Connelly, M. C., Hammill, C., Holbrook, G., Jeffries, C., Singh, B., Schulman, B. A., & Guy, R. K. (2018). Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation. Journal of Medicinal Chemistry, 61(7), 2694-2706. https://doi.org/10.1021/acs.jmedchem.7b01282

@article{b17ed95f61954793bdb86c2802a304a6,

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

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 (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.",

author = "Hammill, \{Jared T.\} and Deepak Bhasin and Scott, \{Daniel C.\} and Jaeki Min and Yizhe Chen and Yan Lu and Lei Yang and Kim, \{Ho Shin\} and Connelly, \{Michele C.\} and Courtney Hammill and Gloria Holbrook and Cynthia Jeffries and Bhuvanesh Singh and Schulman, \{Brenda A.\} and Guy, \{R. Kiplin\}",

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year = "2018",

month = apr,

day = "12",

doi = "10.1021/acs.jmedchem.7b01282",

language = "English",

volume = "61",

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Hammill, JT, Bhasin, D, Scott, DC, Min, J, Chen, Y, Lu, Y, Yang, L, Kim, HS, Connelly, MC, Hammill, C, Holbrook, G, Jeffries, C, Singh, B, Schulman, BA & Guy, RK 2018, 'Discovery of an Orally Bioavailable Inhibitor of Defective in Cullin Neddylation 1 (DCN1)-Mediated Cullin Neddylation', Journal of Medicinal Chemistry, vol. 61, n.º 7, pp. 2694-2706. https://doi.org/10.1021/acs.jmedchem.7b01282

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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

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

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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