Imperial College London
Portrait Picture

DrElenaDe Vita

Faculty of Natural Sciences, Department of Chemistry

 
 
 
//

Contact

 

e.de-vita17 CV

 
 
//

Location

 

Molecular Sciences Research HubWhite City Campus

//

Summary

 

Publications

Citation

BibTex format

@article{De:2019:10.1002/cmdc.201900536,
author = {De, Vita E and Smits, N and van, den Hurk H and Beck, EM and Hewitt, J and Baillie, G and Russell, E and Pannifer, A and Hamon, V and Morrison, A and McElroy, SP and Jones, P and Ignatenko, NA and Gunkel, N and Miller, AK},
doi = {10.1002/cmdc.201900536},
journal = {ChemMedChem},
pages = {79--95},
title = {Synthesis and structure-activity relationships of N-(4-Benzamidino)-oxazolidinones: potent and selective inhibitors of kallikrein-related peptidase 6},
url = {http://dx.doi.org/10.1002/cmdc.201900536},
volume = {15},
year = {2019}
}
Download

RIS format (EndNote, RefMan)

TY  - JOUR
AB  - 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 invitro and potentially invivo.
AU  - De,Vita E
AU  - Smits,N
AU  - van,den Hurk H
AU  - Beck,EM
AU  - Hewitt,J
AU  - Baillie,G
AU  - Russell,E
AU  - Pannifer,A
AU  - Hamon,V
AU  - Morrison,A
AU  - McElroy,SP
AU  - Jones,P
AU  - Ignatenko,NA
AU  - Gunkel,N
AU  - Miller,AK
DO  - 10.1002/cmdc.201900536
EP  - 95
PY  - 2019///
SN  - 0014-827X
SP  - 79
TI  - Synthesis and structure-activity relationships of N-(4-Benzamidino)-oxazolidinones: potent and selective inhibitors of kallikrein-related peptidase 6
T2  - ChemMedChem
UR  - http://dx.doi.org/10.1002/cmdc.201900536
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000496881600001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.201900536
UR  - http://hdl.handle.net/10044/1/93822
VL  - 15
ER  -
Download