title: Synthesis and evaluation of derivatives of the proteasome deubiquitinase inhibitor b-AP15.
abstract: The ubiquitin-proteasome system (UPS) is increasingly recognized as a therapeutic target for the development of anticancer therapies. The success of the 20S proteasome core particle (20S CP) inhibitor bortezomib in the clinical management of multiple myeloma has raised the possibility of identifying other UPS components for therapeutic intervention. We previously identified the small molecule b-AP15 as an inhibitor of 19S proteasome deubiquitinase (DUB) activity. Building upon our previous data, we performed a structure-activity relationship (SAR) study on b-AP15 and identified VLX1570 as an analog with promising properties, including enhanced potency and improved solubility in aqueous solution. In silico modeling was consistent with interaction of VLX1570 with key cysteine residues located at the active sites of the proteasome DUBs USP14 and UCHL5. VLX1570 was found to inhibit proteasome deubiquitinase activity in vitro in a manner consistent with competitive inhibition. Furthermore, using active-site-directed probes, VLX1570 also inhibited proteasome DUB activity in exposed cells. Importantly, VLX1570 did not show inhibitory activity on a panel of recombinant non-proteasome DUBs, on recombinant kinases, or on caspase-3 activity, suggesting that VLX1570 is not an overtly reactive general enzyme inhibitor. Taken together, our data shows the chemical and biological properties of VLX1570 as an optimized proteasome DUB inhibitor.
authors: Department of Medical and Health Sciences, Linköping University, S-581 83, Linköping, Sweden.
authors: Xin
authors: X
authors: Wang
authors: Department of Medical and Health Sciences, Linköping University, S-581 83, Linköping, Sweden.
authors: Pádraig
authors: P
authors: D'Arcy
authors: Department of Molecular Neuroscience, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA.
authors: Thomas R
authors: TR
authors: Caulfield
authors: Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA.
authors: Aneel
authors: A
authors: Paulus
authors: Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA.
authors: Kasyapa
authors: K
authors: Chitta
authors: Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, S-171 76, Stockholm, Sweden.
authors: Chitralekha
authors: C
authors: Mohanty
authors: Department of Immunology, Genetics and Pathology, Section of Oncology, Uppsala University, S-75185, Uppsala, Sweden.
authors: Joachim
authors: J
authors: Gullbo
authors: Department of Cancer Biology, Mayo Clinic, 4500 San Pablo Road South, Jacksonville, FL, 32224, USA.
authors: Asher
authors: A
authors: Chanan-Khan
authors: Department of Medical and Health Sciences, Linköping University, S-581 83, Linköping, Sweden.|Cancer Center Karolinska, Department of Oncology and Pathology, Karolinska Institute, S-171 76, Stockholm, Sweden.
authors: Stig
authors: S
authors: Linder
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D047188:Chalcones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D061988:Proteasome Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D064570:Ubiquitin-Specific Proteases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D047188:Chalcones; D061988:Proteasome Inhibitors; D064570:Ubiquitin-Specific Proteases
keywords: chalcone; deubiquitinase; in silico modeling; inhibitor; lead optimization; proteasome