Development of highly potent inhibitors of the Ras-targeting human acyl protein thioesterases based on substrate similarity design

Christian Hedberg; Frank J Dekker; Marion Rusch; Steffen Renner; Stefan Wetzel; Nachiket Vartak; Claas Gerding-Reimers; Robin S Bon; Philippe I H Bastiaens; Herbert Waldmann

doi:10.1002/anie.201102965

Development of highly potent inhibitors of the Ras-targeting human acyl protein thioesterases based on substrate similarity design

Angew Chem Int Ed Engl. 2011 Oct 10;50(42):9832-7. doi: 10.1002/anie.201102965. Epub 2011 Sep 9.

Authors

Christian Hedberg¹, Frank J Dekker, Marion Rusch, Steffen Renner, Stefan Wetzel, Nachiket Vartak, Claas Gerding-Reimers, Robin S Bon, Philippe I H Bastiaens, Herbert Waldmann

Affiliation

¹ Max-Planck-Institut für molekulare Physiologie, Abt. Chemische Biologie, Dortmund, Germany.

PMID: 21905185
DOI: 10.1002/anie.201102965

Abstract

A matter of common sense: a common recognition motif consisting of a negatively charged group five to six bonds away (red) from the (thio)ester functionality (green) and a positively charged tail group ten to twelve bonds away (blue) was identified in two native acyl protein thioesterase 1 (APT1) substrates. This similarity led to the design of potent inhibitors of the Ras-depalmitoylating enzyme APT1.

MeSH terms

Animals
Cell Line
Dogs
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Lactones / chemical synthesis
Lactones / chemistry
Lactones / pharmacology*
Models, Molecular
Molecular Structure
Structure-Activity Relationship
Substrate Specificity
Thiolester Hydrolases / antagonists & inhibitors*
Thiolester Hydrolases / metabolism
ras Guanine Nucleotide Exchange Factors / metabolism*

Substances

Enzyme Inhibitors
Lactones
ras Guanine Nucleotide Exchange Factors
LYPLA1 protein, human
Thiolester Hydrolases