A Phosphoramidate Strategy Enables Membrane Permeability of a Non-nucleotide Inhibitor of the Prolyl Isomerase Pin1

Daniel M.C. Schwarz; Sarah K. Williams; Maxwell Dillenburg; Carston R. Wagner; Jason E. Gestwicki

doi:10.1021/acsmedchemlett.0c00170

A Phosphoramidate Strategy Enables Membrane Permeability of a Non-nucleotide Inhibitor of the Prolyl Isomerase Pin1

Daniel M.C. Schwarz, Sarah K. Williams, Maxwell Dillenburg, Carston R. Wagner, Jason E. Gestwicki

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4 Scopus citations

Abstract

The membrane permeability of nucleotide-based drugs, such as sofosbuvir (Sovaldi), requires installation of phosphate-caging groups. One strategy, termed "ProTide", masks the anionic phosphate through an N-linked amino ester and an O-linked aromatic phospho-ester, such that release of the active drug requires consecutive enzymatic liberation by an esterase and then a phosphoramidase, such as Hint1. Because Hint1 is known to be selective for nucleotides, it was not clear if the ProTide approach could be deployed for non-nucleotides. Here, we demonstrate that caging of a phosphate-containing inhibitor of the prolyl isomerase Pin1 increases its permeability. Moreover, this compound was processed by both esterase and phosphoramidase activity, releasing the active molecule to bind and inhibit Pin1 in cells. Thus, Hint1 appears to recognize a broader set of substrates than previously appreciated. It seems possible that other potent, but impermeable, phosphate-containing inhibitors might likewise benefit from this approach.

Original language	English (US)
Pages (from-to)	1704-1710
Number of pages	7
Journal	ACS Medicinal Chemistry Letters
Volume	11
Issue number	9
DOIs	https://doi.org/10.1021/acsmedchemlett.0c00170
State	Published - Sep 10 2020

Bibliographical note

Funding Information:
This work was supported by a predoctoral fellowship (1 F31 CA232325-01A1 to D.M.C.S.) and training program Cancer Cell Map Initiative (U54CA209891 to D.M.C.S.) and grants from the University of California Drug Discovery Consortium (UCDDC; to J.E.G.), the UCSF InVent Fund (to J.E.G.), and the University of Minnesota Foundation (to C.R.W.). The authors thank Bryan Dunyak for early contributions to the project.

Publisher Copyright:
Copyright © 2020 American Chemical Society.

Keywords

Hint1
PPIase
ProTide
oncology
phosphate-containing
pro-drug

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title = "A Phosphoramidate Strategy Enables Membrane Permeability of a Non-nucleotide Inhibitor of the Prolyl Isomerase Pin1",

abstract = "The membrane permeability of nucleotide-based drugs, such as sofosbuvir (Sovaldi), requires installation of phosphate-caging groups. One strategy, termed {"}ProTide{"}, masks the anionic phosphate through an N-linked amino ester and an O-linked aromatic phospho-ester, such that release of the active drug requires consecutive enzymatic liberation by an esterase and then a phosphoramidase, such as Hint1. Because Hint1 is known to be selective for nucleotides, it was not clear if the ProTide approach could be deployed for non-nucleotides. Here, we demonstrate that caging of a phosphate-containing inhibitor of the prolyl isomerase Pin1 increases its permeability. Moreover, this compound was processed by both esterase and phosphoramidase activity, releasing the active molecule to bind and inhibit Pin1 in cells. Thus, Hint1 appears to recognize a broader set of substrates than previously appreciated. It seems possible that other potent, but impermeable, phosphate-containing inhibitors might likewise benefit from this approach.",

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note = "Funding Information: This work was supported by a predoctoral fellowship (1 F31 CA232325-01A1 to D.M.C.S.) and training program Cancer Cell Map Initiative (U54CA209891 to D.M.C.S.) and grants from the University of California Drug Discovery Consortium (UCDDC; to J.E.G.), the UCSF InVent Fund (to J.E.G.), and the University of Minnesota Foundation (to C.R.W.). The authors thank Bryan Dunyak for early contributions to the project. Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",

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N2 - The membrane permeability of nucleotide-based drugs, such as sofosbuvir (Sovaldi), requires installation of phosphate-caging groups. One strategy, termed "ProTide", masks the anionic phosphate through an N-linked amino ester and an O-linked aromatic phospho-ester, such that release of the active drug requires consecutive enzymatic liberation by an esterase and then a phosphoramidase, such as Hint1. Because Hint1 is known to be selective for nucleotides, it was not clear if the ProTide approach could be deployed for non-nucleotides. Here, we demonstrate that caging of a phosphate-containing inhibitor of the prolyl isomerase Pin1 increases its permeability. Moreover, this compound was processed by both esterase and phosphoramidase activity, releasing the active molecule to bind and inhibit Pin1 in cells. Thus, Hint1 appears to recognize a broader set of substrates than previously appreciated. It seems possible that other potent, but impermeable, phosphate-containing inhibitors might likewise benefit from this approach.

AB - The membrane permeability of nucleotide-based drugs, such as sofosbuvir (Sovaldi), requires installation of phosphate-caging groups. One strategy, termed "ProTide", masks the anionic phosphate through an N-linked amino ester and an O-linked aromatic phospho-ester, such that release of the active drug requires consecutive enzymatic liberation by an esterase and then a phosphoramidase, such as Hint1. Because Hint1 is known to be selective for nucleotides, it was not clear if the ProTide approach could be deployed for non-nucleotides. Here, we demonstrate that caging of a phosphate-containing inhibitor of the prolyl isomerase Pin1 increases its permeability. Moreover, this compound was processed by both esterase and phosphoramidase activity, releasing the active molecule to bind and inhibit Pin1 in cells. Thus, Hint1 appears to recognize a broader set of substrates than previously appreciated. It seems possible that other potent, but impermeable, phosphate-containing inhibitors might likewise benefit from this approach.

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A Phosphoramidate Strategy Enables Membrane Permeability of a Non-nucleotide Inhibitor of the Prolyl Isomerase Pin1

Abstract

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