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Tomala, M.D.* ; Magiera-Mularz, K.* ; Kubica, K.* ; Krzanik, S.* ; Zieba, B.* ; Musielak, B.* ; Pustula, M.* ; Popowicz, G.M. ; Sattler, M. ; Dubin, G.* ; Skalniak, L.* ; Holak, T.A.*

Identification of small-molecule inhibitors of USP2a.

Eur. J. Med. Chem. 150, 261-267 (2018)
Postprint DOI PMC
Open Access Green
USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a. Iterations of fragment combination and structure-driven design identified two 5-(2-thienyl)-3-isoxazoles as the inhibitors of the USP2a-ubiquitin protein-protein interaction. The affinity of these molecules for the catalytic domain of USP2a parallels their ability to interfere with USP2a binding to ubiquitin in vitro. Altogether, our results establish the 5-(2-thienyl)-3-isoxazole pharmacophore as an attractive starting point for lead optimization.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Deubiquitinase ; Ubiquitin ; Small-molecular Inhibitors ; Heterocyclics ; Anticancer
Sprache
Veröffentlichungsjahr 2018
HGF-Berichtsjahr 2018
ISSN (print) / ISBN 0223-5234
e-ISSN 1768-3254
Zeitschrift European Journal of Medicinal Chemistry
Quellenangaben Band: 150, Heft: , Seiten: 261-267 Artikelnummer: , Supplement: ,
Verlag Elsevier
Verlagsort Amsterdam [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Structural Biology (STB)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-503000-001
DOI 10.1016/j.ejmech.2018.03.009
WOS ID WOS:000430891400019
Scopus ID 85043358576
PubMed ID 29529503
Erfassungsdatum 2018-05-24
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