2. Academic Validation
  3. A fragment-like approach to PYCR1 inhibition

A fragment-like approach to PYCR1 inhibition

  • Bioorg Med Chem Lett. 2019 Sep 15;29(18):2626-2631. doi: 10.1016/j.bmcl.2019.07.047.
Kirsty Milne 1,  Jianhui Sun 2,  Esther A Zaal 3,  Jenna Mowat 1,  Patrick H N Celie 4,  Alexander Fish 4,  Celia R Berkers 5,  Giuseppe Forlani 6,  Fabricio Loayza-Puch 7,  Craig Jamieson 8,  Reuven Agami 9
Affiliations

Affiliations

  • 1 Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde, Glasgow G1 1XL, United Kingdom.
  • 2 H5 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
  • 3 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
  • 4 H5 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands; NKI Protein Facility, Division of Biochemistry, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
  • 5 Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands; Department of Biochemistry and Cell Biology, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 2, 3584 CM Utrecht, The Netherlands.
  • 6 Department of Life Science and Biotechnology, University of Ferrara, 44121 Ferrara, Italy.
  • 7 H5 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands. Electronic address: [email protected].
  • 8 Department of Pure and Applied Chemistry, Thomas Graham Building, University of Strathclyde, Glasgow G1 1XL, United Kingdom. Electronic address: [email protected].
  • 9 H5 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, 121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands; Department of Molecular Genetics, Erasmus MC, Rotterdam University, The Netherlands. Electronic address: [email protected].
PMID: 31362921 DOI: 10.1016/j.bmcl.2019.07.047
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-126271
    99.79%, PYCR1 Inhibitor