PMID- 31362921
OWN - NLM
STAT- MEDLINE
DCOM- 20201015
LR  - 20231213
IS  - 1464-3405 (Electronic)
IS  - 0960-894X (Linking)
VI  - 29
IP  - 18
DP  - 2019 Sep 15
TI  - A fragment-like approach to PYCR1 inhibition.
PG  - 2626-2631
LID - S0960-894X(19)30503-7 [pii]
LID - 10.1016/j.bmcl.2019.07.047 [doi]
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 (IC(50) = 8.8 microM) and pathway relevant effects in 
      cell-based assays.
CI  - Copyright (c) 2019 Elsevier Ltd. All rights reserved.
FAU - Milne, Kirsty
AU  - Milne K
AD  - Department of Pure and Applied Chemistry, Thomas Graham Building, University of 
      Strathclyde, Glasgow G1 1XL, United Kingdom.
FAU - Sun, Jianhui
AU  - Sun J
AD  - H5 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, 
      121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands.
FAU - Zaal, Esther A
AU  - Zaal EA
AD  - Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular 
      Research, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands.
FAU - Mowat, Jenna
AU  - Mowat J
AD  - Department of Pure and Applied Chemistry, Thomas Graham Building, University of 
      Strathclyde, Glasgow G1 1XL, United Kingdom.
FAU - Celie, Patrick H N
AU  - Celie PHN
AD  - 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.
FAU - Fish, Alexander
AU  - Fish A
AD  - 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.
FAU - Berkers, Celia R
AU  - Berkers CR
AD  - 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.
FAU - Forlani, Giuseppe
AU  - Forlani G
AD  - Department of Life Science and Biotechnology, University of Ferrara, 44121 
      Ferrara, Italy.
FAU - Loayza-Puch, Fabricio
AU  - Loayza-Puch F
AD  - H5 Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, 
      121 Plesmanlaan, 1066 CX Amsterdam, The Netherlands. Electronic address: 
      f.loayza-puch@dkfz-heidelberg.de.
FAU - Jamieson, Craig
AU  - Jamieson C
AD  - Department of Pure and Applied Chemistry, Thomas Graham Building, University of 
      Strathclyde, Glasgow G1 1XL, United Kingdom. Electronic address: 
      craig.jamieson@strath.ac.uk.
FAU - Agami, Reuven
AU  - Agami R
AD  - 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: 
      r.agami@nki.nl.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190725
PL  - England
TA  - Bioorg Med Chem Lett
JT  - Bioorganic & medicinal chemistry letters
JID - 9107377
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Small Molecule Libraries)
RN  - 9MV14S8G3E (Pargyline)
RN  - EC 1.5.1.- (Pyrroline Carboxylate Reductases)
SB  - IM
MH  - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Screening Assays, Antitumor
MH  - Enzyme Inhibitors/chemical synthesis/chemistry/*pharmacology
MH  - Humans
MH  - Molecular Structure
MH  - Pargyline/chemical synthesis/chemistry/*pharmacology
MH  - Pyrroline Carboxylate Reductases/*antagonists & inhibitors/metabolism
MH  - Small Molecule Libraries/chemical synthesis/chemistry/*pharmacology
MH  - Structure-Activity Relationship
MH  - delta-1-Pyrroline-5-Carboxylate Reductase
OTO - NOTNLM
OT  - Fragment-based drug discovery
OT  - Inhibitor
OT  - Oncology
OT  - Proline modulation
OT  - Tool compound
EDAT- 2019/08/01 06:00
MHDA- 2020/10/21 06:00
CRDT- 2019/08/01 06:00
PHST- 2019/06/19 00:00 [received]
PHST- 2019/07/23 00:00 [revised]
PHST- 2019/07/24 00:00 [accepted]
PHST- 2019/08/01 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2019/08/01 06:00 [entrez]
AID - S0960-894X(19)30503-7 [pii]
AID - 10.1016/j.bmcl.2019.07.047 [doi]
PST - ppublish
SO  - Bioorg Med Chem Lett. 2019 Sep 15;29(18):2626-2631. doi: 
      10.1016/j.bmcl.2019.07.047. Epub 2019 Jul 25.