Title : Affinity-Based Selectivity Profiling of an In-Class Selective Competitive Inhibitor of Acyl Protein Thioesterase 2 - Won_2017_ACS.Med.Chem.Lett_8_215 |
Author(s) : Won SJ , Eschweiler JD , Majmudar JD , Chong FS , Hwang SY , Ruotolo BT , Martin BR |
Ref : ACS Med Chem Lett , 8 :215 , 2017 |
Abstract :
Activity-based protein profiling (ABPP) has revolutionized the discovery and optimization of active-site ligands across distinct enzyme families, providing a robust platform for in-class selectivity profiling. Nonetheless, this approach is less straightforward for profiling reversible inhibitors and does not access proteins outside the ABPP probe's target profile. While the active-site competitive acyl protein thioesterase 2 inhibitor ML349 (Ki = 120 nM) is highly selective within the serine hydrolase enzyme family, it could still interact with other cellular targets. Here we present a chemoproteomic workflow to enrich and profile candidate ML349-binding proteins. In human cell lysates, biotinylated-ML349 enriches a recurring set of proteins, including metabolite kinases and flavin-dependent oxidoreductases that are potentially enhanced by avidity-driven multimeric interactions. Confirmatory assays by native mass spectrometry and fluorescence polarization quickly rank-ordered these weak off-targets, providing justification to explore ligand interactions and stoichiometry beyond ABPP. |
PubMedSearch : Won_2017_ACS.Med.Chem.Lett_8_215 |
PubMedID: 28197315 |
Won SJ, Eschweiler JD, Majmudar JD, Chong FS, Hwang SY, Ruotolo BT, Martin BR (2017)
Affinity-Based Selectivity Profiling of an In-Class Selective Competitive Inhibitor of Acyl Protein Thioesterase 2
ACS Med Chem Lett
8 :215
Won SJ, Eschweiler JD, Majmudar JD, Chong FS, Hwang SY, Ruotolo BT, Martin BR (2017)
ACS Med Chem Lett
8 :215