Identification of potent inhibitors of the sortilin-progranulin interaction

Shawn J. Stachel; Anthony T. Ginnetti; Scott A. Johnson; Paige Cramer; Yi Wang; Marina Bukhtiyarova; Daniel Krosky; Craig Stump; Danielle M. Hurzy; Kelly Ann Schlegel; Andrew J. Cooke; Samantha Allen; Gregory O'Donnell; Michael Ziebell; Gopal Parthasarathy; Krista L. Getty; Thu Ho; Yangsi Ou; Aneta Jovanovska; Steve S. Carroll; Mark Pausch; Kevin Lumb; Scott D. Mosser; Bhavya Voleti; Daniel J. Klein; Stephen M. Soisson; Celina Zerbinatti; Paul J. Coleman

doi:10.1016/j.bmcl.2020.127403

Identification of potent inhibitors of the sortilin-progranulin interaction

Shawn J. Stachel, Anthony T. Ginnetti, Scott A. Johnson, Paige Cramer, Yi Wang, Marina Bukhtiyarova, Daniel Krosky, Craig Stump, Danielle M. Hurzy, Kelly Ann Schlegel, Andrew J. Cooke, Samantha Allen, Gregory O'Donnell, Michael Ziebell, Gopal Parthasarathy, Krista L. Getty, Thu Ho, Yangsi Ou, Aneta Jovanovska, Steve S. CarrollMark Pausch, Kevin Lumb, Scott D. Mosser, Bhavya Voleti, Daniel J. Klein, Stephen M. Soisson, Celina Zerbinatti, Paul J. Coleman

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.

Original language	English (US)
Article number	127403
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	30
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2020.127403
State	Published - Sep 1 2020
Externally published	Yes

Keywords

Progranulin
Protein-protein interaction inhibitor
Sortilin
Structure activity relationship

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2020.127403

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Stachel, S. J., Ginnetti, A. T., Johnson, S. A., Cramer, P., Wang, Y., Bukhtiyarova, M., Krosky, D., Stump, C., Hurzy, D. M., Schlegel, K. A., Cooke, A. J., Allen, S., O'Donnell, G., Ziebell, M., Parthasarathy, G., Getty, K. L., Ho, T., Ou, Y., Jovanovska, A., ... Coleman, P. J. (2020). Identification of potent inhibitors of the sortilin-progranulin interaction. Bioorganic and Medicinal Chemistry Letters, 30(17), Article 127403. https://doi.org/10.1016/j.bmcl.2020.127403

Stachel, SJ, Ginnetti, AT, Johnson, SA, Cramer, P, Wang, Y, Bukhtiyarova, M, Krosky, D, Stump, C, Hurzy, DM, Schlegel, KA, Cooke, AJ, Allen, S, O'Donnell, G, Ziebell, M, Parthasarathy, G, Getty, KL, Ho, T, Ou, Y, Jovanovska, A, Carroll, SS, Pausch, M, Lumb, K, Mosser, SD, Voleti, B, Klein, DJ, Soisson, SM, Zerbinatti, C & Coleman, PJ 2020, 'Identification of potent inhibitors of the sortilin-progranulin interaction', Bioorganic and Medicinal Chemistry Letters, vol. 30, no. 17, 127403. https://doi.org/10.1016/j.bmcl.2020.127403

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title = "Identification of potent inhibitors of the sortilin-progranulin interaction",

abstract = "High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.",

keywords = "Progranulin, Protein-protein interaction inhibitor, Sortilin, Structure activity relationship",

author = "Stachel, {Shawn J.} and Ginnetti, {Anthony T.} and Johnson, {Scott A.} and Paige Cramer and Yi Wang and Marina Bukhtiyarova and Daniel Krosky and Craig Stump and Hurzy, {Danielle M.} and Schlegel, {Kelly Ann} and Cooke, {Andrew J.} and Samantha Allen and Gregory O'Donnell and Michael Ziebell and Gopal Parthasarathy and Getty, {Krista L.} and Thu Ho and Yangsi Ou and Aneta Jovanovska and Carroll, {Steve S.} and Mark Pausch and Kevin Lumb and Mosser, {Scott D.} and Bhavya Voleti and Klein, {Daniel J.} and Soisson, {Stephen M.} and Celina Zerbinatti and Coleman, {Paul J.}",

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year = "2020",

month = sep,

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doi = "10.1016/j.bmcl.2020.127403",

language = "English (US)",

volume = "30",

journal = "Bioorganic and Medicinal Chemistry Letters",

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T1 - Identification of potent inhibitors of the sortilin-progranulin interaction

AU - Stachel, Shawn J.

AU - Ginnetti, Anthony T.

AU - Johnson, Scott A.

AU - Cramer, Paige

AU - Wang, Yi

AU - Bukhtiyarova, Marina

AU - Krosky, Daniel

AU - Stump, Craig

AU - Hurzy, Danielle M.

AU - Schlegel, Kelly Ann

AU - Cooke, Andrew J.

AU - Allen, Samantha

AU - O'Donnell, Gregory

AU - Ziebell, Michael

AU - Parthasarathy, Gopal

AU - Getty, Krista L.

AU - Ho, Thu

AU - Ou, Yangsi

AU - Jovanovska, Aneta

AU - Carroll, Steve S.

AU - Pausch, Mark

AU - Lumb, Kevin

AU - Mosser, Scott D.

AU - Voleti, Bhavya

AU - Klein, Daniel J.

AU - Soisson, Stephen M.

AU - Zerbinatti, Celina

AU - Coleman, Paul J.

PY - 2020/9/1

Y1 - 2020/9/1

N2 - High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.

AB - High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.

KW - Progranulin

KW - Protein-protein interaction inhibitor

KW - Sortilin

KW - Structure activity relationship

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 17

M1 - 127403

ER -

Identification of potent inhibitors of the sortilin-progranulin interaction

Abstract

Keywords

ASJC Scopus subject areas

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