A fragment-like approach to PYCR1 inhibition

Kirsty Milne; Jianhui Sun; Esther A. Zaal; Jenna Mowat; Patrick H.N. Celie; Alexander Fish; Celia R. Berkers; Giuseppe Forlani; Fabricio Loayza-Puch; Craig Jamieson; Reuven Agami

doi:10.1016/j.bmcl.2019.07.047

A fragment-like approach to PYCR1 inhibition

Kirsty Milne
, Jianhui Sun
, Esther A. Zaal
, Jenna Mowat
, Patrick H.N. Celie
, Alexander Fish
, Celia R. Berkers
, Giuseppe Forlani
, Fabricio Loayza-Puch^*
, Craig Jamieson
, Reuven Agami

^*Corresponding author for this work

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

Abstract

Pyrroline-5-carboxylate reductase 1 (PYCR1) is the final enzyme involved in the biosynthesis of proline and has been found to be upregulated in various forms of cancer. Due to the role of proline in maintaining the redox balance of cells and preventing apoptosis, PYCR1 is emerging as an attractive oncology target. Previous PYCR1 knockout studies led to a reduction in tumor growth. Accordingly, a small molecule inhibitor of PYCR1 could lead to new treatments for cancer, and a focused screening effort identified pargyline as a fragment-like hit. We report the design and synthesis of the first tool compounds as PYCR1 inhibitors, derived from pargyline, which were assayed to assess their ability to attenuate the production of proline. Structural activity studies have revealed the key determinants of activity, with the most potent compound (4) showing improved activity in vitro in enzyme (IC₅₀ = 8.8 µM) and pathway relevant effects in cell-based assays.

Original language	English
Pages (from-to)	2626-2631
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	29
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2019.07.047
Publication status	Published - 15 Sept 2019

Funding

GlaxoSmithKline/Engineering and Physical Sciences Research Council UK (KM); The Dutch Cancer Society KWF 2017-11037 (RA). The National Mass Spectrometry Facility at Swansea University for provision of HRMS data. Appendix A

Keywords

Fragment-based drug discovery
Inhibitor
Oncology
Proline modulation
Tool compound

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bmcl.2019.07.047

fragmentFinal published version, 1.38 MBLicence: Taverne

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title = "A fragment-like approach to PYCR1 inhibition",

abstract = "Pyrroline-5-carboxylate reductase 1 (PYCR1) is the final enzyme involved in the biosynthesis of proline and has been found to be upregulated in various forms of cancer. Due to the role of proline in maintaining the redox balance of cells and preventing apoptosis, PYCR1 is emerging as an attractive oncology target. Previous PYCR1 knockout studies led to a reduction in tumor growth. Accordingly, a small molecule inhibitor of PYCR1 could lead to new treatments for cancer, and a focused screening effort identified pargyline as a fragment-like hit. We report the design and synthesis of the first tool compounds as PYCR1 inhibitors, derived from pargyline, which were assayed to assess their ability to attenuate the production of proline. Structural activity studies have revealed the key determinants of activity, with the most potent compound (4) showing improved activity in vitro in enzyme (IC50 = 8.8 µM) and pathway relevant effects in cell-based assays.",

keywords = "Fragment-based drug discovery, Inhibitor, Oncology, Proline modulation, Tool compound",

author = "Kirsty Milne and Jianhui Sun and Zaal, \{Esther A.\} and Jenna Mowat and Celie, \{Patrick H.N.\} and Alexander Fish and Berkers, \{Celia R.\} and Giuseppe Forlani and Fabricio Loayza-Puch and Craig Jamieson and Reuven Agami",

year = "2019",

month = sep,

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doi = "10.1016/j.bmcl.2019.07.047",

language = "English",

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T1 - A fragment-like approach to PYCR1 inhibition

AU - Milne, Kirsty

AU - Sun, Jianhui

AU - Zaal, Esther A.

AU - Mowat, Jenna

AU - Celie, Patrick H.N.

AU - Fish, Alexander

AU - Berkers, Celia R.

AU - Forlani, Giuseppe

AU - Loayza-Puch, Fabricio

AU - Jamieson, Craig

AU - Agami, Reuven

PY - 2019/9/15

Y1 - 2019/9/15

N2 - Pyrroline-5-carboxylate reductase 1 (PYCR1) is the final enzyme involved in the biosynthesis of proline and has been found to be upregulated in various forms of cancer. Due to the role of proline in maintaining the redox balance of cells and preventing apoptosis, PYCR1 is emerging as an attractive oncology target. Previous PYCR1 knockout studies led to a reduction in tumor growth. Accordingly, a small molecule inhibitor of PYCR1 could lead to new treatments for cancer, and a focused screening effort identified pargyline as a fragment-like hit. We report the design and synthesis of the first tool compounds as PYCR1 inhibitors, derived from pargyline, which were assayed to assess their ability to attenuate the production of proline. Structural activity studies have revealed the key determinants of activity, with the most potent compound (4) showing improved activity in vitro in enzyme (IC50 = 8.8 µM) and pathway relevant effects in cell-based assays.

AB - Pyrroline-5-carboxylate reductase 1 (PYCR1) is the final enzyme involved in the biosynthesis of proline and has been found to be upregulated in various forms of cancer. Due to the role of proline in maintaining the redox balance of cells and preventing apoptosis, PYCR1 is emerging as an attractive oncology target. Previous PYCR1 knockout studies led to a reduction in tumor growth. Accordingly, a small molecule inhibitor of PYCR1 could lead to new treatments for cancer, and a focused screening effort identified pargyline as a fragment-like hit. We report the design and synthesis of the first tool compounds as PYCR1 inhibitors, derived from pargyline, which were assayed to assess their ability to attenuate the production of proline. Structural activity studies have revealed the key determinants of activity, with the most potent compound (4) showing improved activity in vitro in enzyme (IC50 = 8.8 µM) and pathway relevant effects in cell-based assays.

KW - Fragment-based drug discovery

KW - Inhibitor

KW - Oncology

KW - Proline modulation

KW - Tool compound

UR - https://www.scopus.com/pages/publications/85069684729

U2 - 10.1016/j.bmcl.2019.07.047

DO - 10.1016/j.bmcl.2019.07.047

M3 - Article

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AN - SCOPUS:85069684729

SN - 0960-894X

VL - 29

SP - 2626

EP - 2631

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 18

ER -

A fragment-like approach to PYCR1 inhibition

Abstract

Funding

Keywords

UN SDGs

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