Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors

Michael E. Stokes; Matthew D. Surman; Veronica Calvo; David Surguladze; An Hu Li; Jennifer Gasparek; Matthew Betzenhauser; Guangyu Zhu; Hongwen Du; Alan C. Rigby; Mark J. Mulvihill

doi:10.3390/pharmaceutics14102233

Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors

Michael E. Stokes, Matthew D. Surman, Veronica Calvo, David Surguladze, An Hu Li, Jennifer Gasparek, Matthew Betzenhauser, Guangyu Zhu, Hongwen Du, Alan C. Rigby, Mark J. Mulvihill

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

7 Scopus citations

Abstract

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice.

Original language	English
Article number	2233
Journal	Pharmaceutics
Volume	14
Issue number	10
DOIs	https://doi.org/10.3390/pharmaceutics14102233
State	Published - Oct 2022
Externally published	Yes

Keywords

ER stress
PERK
UPR
cancer
diabetes
inhibitor
kinase
small molecule
structure–activity-relationship (SAR)

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10.3390/pharmaceutics14102233

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title = "Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors",

abstract = "The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice.",

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doi = "10.3390/pharmaceutics14102233",

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volume = "14",

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AU - Stokes, Michael E.

AU - Surman, Matthew D.

AU - Calvo, Veronica

AU - Surguladze, David

AU - Li, An Hu

AU - Gasparek, Jennifer

AU - Betzenhauser, Matthew

AU - Zhu, Guangyu

AU - Du, Hongwen

AU - Rigby, Alan C.

AU - Mulvihill, Mark J.

PY - 2022/10

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KW - ER stress

KW - PERK

KW - UPR

KW - cancer

KW - diabetes

KW - inhibitor

KW - kinase

KW - small molecule

KW - structure–activity-relationship (SAR)

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JO - Pharmaceutics

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Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors

Abstract

Keywords

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