Tags

Type your tag names separated by a space and hit enter

Identification of small-molecule inhibitors of USP2a.
Eur J Med Chem 2018; 150:261-267EJ

Abstract

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.

Authors+Show Affiliations

Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Krakow, Poland.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Krakow, Poland.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Krakow, Poland.Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Krakow, Poland.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Krakow, Poland.Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.Institute of Structural Biology, Helmholtz Zentrum München, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387, Krakow, Poland.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Krakow, Poland.Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387, Krakow, Poland. Electronic address: holak@chemia.uj.edu.pl.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29529503

Citation

Tomala, Marcin D., et al. "Identification of Small-molecule Inhibitors of USP2a." European Journal of Medicinal Chemistry, vol. 150, 2018, pp. 261-267.
Tomala MD, Magiera-Mularz K, Kubica K, et al. Identification of small-molecule inhibitors of USP2a. Eur J Med Chem. 2018;150:261-267.
Tomala, M. D., Magiera-Mularz, K., Kubica, K., Krzanik, S., Zieba, B., Musielak, B., ... Holak, T. A. (2018). Identification of small-molecule inhibitors of USP2a. European Journal of Medicinal Chemistry, 150, pp. 261-267. doi:10.1016/j.ejmech.2018.03.009.
Tomala MD, et al. Identification of Small-molecule Inhibitors of USP2a. Eur J Med Chem. 2018 Apr 25;150:261-267. PubMed PMID: 29529503.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Identification of small-molecule inhibitors of USP2a. AU - Tomala,Marcin D, AU - Magiera-Mularz,Katarzyna, AU - Kubica,Katarzyna, AU - Krzanik,Sylwia, AU - Zieba,Bartosz, AU - Musielak,Bogdan, AU - Pustula,Marcin, AU - Popowicz,Grzegorz M, AU - Sattler,Michael, AU - Dubin,Grzegorz, AU - Skalniak,Lukasz, AU - Holak,Tad A, Y1 - 2018/03/05/ PY - 2017/10/24/received PY - 2018/02/15/revised PY - 2018/03/01/accepted PY - 2018/3/13/pubmed PY - 2018/4/27/medline PY - 2018/3/13/entrez KW - Anticancer KW - Deubiquitinase KW - Heterocyclics KW - Small-molecular inhibitors KW - Ubiquitin SP - 261 EP - 267 JF - European journal of medicinal chemistry JO - Eur J Med Chem VL - 150 N2 - 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. SN - 1768-3254 UR - https://www.unboundmedicine.com/medline/citation/29529503/Identification_of_small-molecule_inhibitors_of_USP2a L2 - https://linkinghub.elsevier.com/retrieve/pii/S0223-5234(18)30244-7 DB - PRIME DP - Unbound Medicine ER -