Synthesis and Structure-Activity Relationships of N-(4-Benzamidino)-Oxazolidinones: Potent and Selective Inhibitors of Kallikrein-Related Peptidase 6.
Binding Sites
Cell Movement
/ drug effects
Cytochrome P-450 Enzyme System
/ metabolism
HCT116 Cells
Half-Life
Humans
Inhibitory Concentration 50
Kallikreins
/ antagonists & inhibitors
Molecular Docking Simulation
Neuroprotective Agents
/ chemical synthesis
Oxazolidinones
/ chemistry
Stereoisomerism
Structure-Activity Relationship
Drug Discovery
High-throughput screening
Medicinal Chemistry
Protease inhibitors
Structure-activity relationship
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
07 01 2020
07 01 2020
Historique:
received:
19
09
2019
revised:
23
10
2019
pubmed:
2
11
2019
medline:
29
1
2021
entrez:
2
11
2019
Statut:
ppublish
Résumé
Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins. Aberrant expression of KLK6 has been found in different cancers and neurodegenerative diseases, and KLK6 is currently studied as a potential target in these pathologies. We report a novel series of KLK6 inhibitors discovered in a high-throughput screen within the European Lead Factory program. Structure-guided design based on docking studies enabled rapid progression of a hit cluster to inhibitors with improved potency, selectivity and pharmacokinetic properties. In particular, inhibitors 32 ((5R)-3-(4-carbamimidoylphenyl)-N-((S)-1-(naphthalen-1-yl)propyl)-2-oxooxazolidine-5-carboxamide) and 34 ((5R)-3-(6-carbamimidoylpyridin-3-yl)-N-((1S)-1-(naphthalen-1-yl)propyl)-2-oxooxazolidine-5-carboxamide) have single-digit nanomolar potency against KLK6, with over 25-fold and 100-fold selectivities against the closely related enzyme trypsin, respectively. The most potent compound, 32, effectively reduces KLK6-dependent invasion of HCT116 cells. The high potency in combination with good solubility and low clearance of 32 make it a good chemical probe for KLK6 target validation in vitro and potentially in vivo.
Identifiants
pubmed: 31675166
doi: 10.1002/cmdc.201900536
pmc: PMC7004151
doi:
Substances chimiques
Neuroprotective Agents
0
Oxazolidinones
0
Cytochrome P-450 Enzyme System
9035-51-2
KLK6 protein, human
EC 3.4.21.-
Kallikreins
EC 3.4.21.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
79-95Subventions
Organisme : NCI NIH HHS
ID : R01 CA157595
Pays : United States
Informations de copyright
©2019 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
Références
J Biol Chem. 2007 Nov 2;282(44):31852-64
pubmed: 17823117
J Biol Chem. 2006 Feb 10;281(6):3116-26
pubmed: 16321973
Neoplasia. 2017 May;19(5):396-411
pubmed: 28431272
Br J Plast Surg. 1999 Apr;52(3):209-13
pubmed: 10474473
ChemMedChem. 2020 Jan 7;15(1):79-95
pubmed: 31675166
Biol Chem. 2015 Jan;396(1):45-52
pubmed: 25153237
Chem Biol. 2001 Nov;8(11):1107-21
pubmed: 11731301
Acc Chem Res. 2002 Nov;35(11):984-95
pubmed: 12437323
Protein Sci. 2008 Apr;17(4):664-72
pubmed: 18359858
Mol Med. 1996 Sep;2(5):624-36
pubmed: 8898378
FASEB J. 2004 May;18(7):920-2
pubmed: 15033932
ACS Med Chem Lett. 2012 Jan 11;3(2):159-64
pubmed: 24900446
Hum Mol Genet. 2003 Oct 15;12(20):2625-35
pubmed: 12928483
Mol Cancer. 2015 May 20;14:107
pubmed: 25990935
ACS Med Chem Lett. 2014 Jan 13;5(4):373-7
pubmed: 24900843
Biochim Biophys Acta. 1997 Jan 3;1350(1):11-4
pubmed: 9003450
J Mol Biol. 2006 Oct 6;362(5):1094-107
pubmed: 16950394
Endocr Rev. 2001 Apr;22(2):184-204
pubmed: 11294823
Biochem Biophys Res Commun. 2003 Aug 8;307(4):948-55
pubmed: 12878203
Psychiatry Clin Neurosci. 2000 Aug;54(4):419-26
pubmed: 10997858
Alzheimers Res Ther. 2018 Jan 29;10(1):9
pubmed: 29378650
J Biol Chem. 2006 Oct 27;281(43):32095-112
pubmed: 16885167
J Neurosci. 1997 Nov 1;17(21):8156-68
pubmed: 9334391
Curr Protein Pept Sci. 2009 Aug;10(4):297-307
pubmed: 19689354
Protein Sci. 2008 Nov;17(11):1998-2007
pubmed: 18697857
J Biol Chem. 1997 Oct 3;272(40):25135-42
pubmed: 9312124
Biol Chem. 2013 Jan;394(1):137-47
pubmed: 23241590
J Biol Chem. 2006 Sep 1;281(35):25678-88
pubmed: 16740631
Bioorg Med Chem Lett. 2012 Apr 1;22(7):2450-5
pubmed: 22386244
Eur J Neurosci. 2006 Sep;24(5):1457-69
pubmed: 16987227
J Med Chem. 2018 Oct 11;61(19):8859-8874
pubmed: 30212625
J Biol Chem. 1999 Feb 12;274(7):4220-4
pubmed: 9933620
J Invest Dermatol. 2011 Nov;131(11):2281-8
pubmed: 21753781
Nat Rev Drug Discov. 2015 Mar;14(3):183-202
pubmed: 25698643
Biol Chem. 2018 Sep 25;399(9):1073-1078
pubmed: 29641412