Abstract
Recent evidence suggests that several deubiquitinases (DUB) are overexpressed or activated in tumor cells and many contribute to the transformed phenotype. Agents with DUB inhibitory activity may therefore have therapeutic value. In this study, we describe the mechanism of action of WP1130, a small molecule derived from a compound with Janus-activated kinase 2 (JAK2) kinase inhibitory activity. WP1130 induces rapid accumulation of polyubiquitinated (K48/K63-linked) proteins into juxtanuclear aggresomes, without affecting 20S proteasome activity. WP1130 acts as a partly selective DUB inhibitor, directly inhibiting DUB activity of USP9x, USP5, USP14, and UCH37, which are known to regulate survival protein stability and 26S proteasome function. WP1130-mediated inhibition of tumor-activated DUBs results in downregulation of antiapoptotic and upregulation of proapoptotic proteins, such as MCL-1 and p53. Our results show that chemical modification of a previously described JAK2 inhibitor results in the unexpected discovery of a novel DUB inhibitor with a unique antitumor mechanism.
Highlights
Ubiquitination is a covalent posttranslational modification of cellular proteins involving a complex enzymatic cascade
Our preliminary studies showed that mantle cell lymphoma Z138 cells displayed high apoptotic sensitivity to WP1130 (IC50 ∼1 μmol/L), evident by the appearance of cleaved poly(ADP-ribose) polymerase (PARP) after 2 to 4 hours of treatment
Direct comparison of WP1130 with AG490 or bortezomib, which is clinically active in mantle cell tumors, illustrated distinctions in the apoptotic onset and activity of each compound (Fig. 1A)
Summary
Ubiquitination is a covalent posttranslational modification of cellular proteins involving a complex enzymatic cascade. Emerging evidence suggests that many enzymes of the ubiquitination cascade are differentially expressed or activated in several diseases, including cancer, and may be appropriate therapeutic targets. Small molecules that affect protein ubiquitination and induce tumor cell apoptosis through inhibition of the ubiquitin conjugation or deconjugation enzymes have been described. Novel compounds that affect E1-activating enzyme activity [1,2,3] or E3 ligase substrate recognition such as HDM2 and TRAF6 [4, 5] have been described, and preclinical antitumor activity has been reported. Bortezomib is one example of such compound that inhibits the chymotryptic-like activity of the 20S proteasome, resulting in the accumulation of ubiquiti-
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
