WP1130

WP1130 is a second-generation tyrphostin derivative initially identified as a JAK2 signaling inhibitor through JAK2 ubiquitination that reduces STAT activation stimulated by cytokines (such as IL-6 and IL-3) through the rapid down-regulation of upstream JAK kinases. WP1130 has also been identified as a partially selective cell permeable deubiquitinating enzyme/deubiquitinase (DUB) inhibitor that directly inhibits DUB activity of USP9x, USP5, USP14, USP24, UCH37, UCHL1 and UCHL5, leading to rapid accumulation of polyubiquitinated (K48/K63-linked) proteins into juxtanuclear aggresomes and tumor cell apoptosis, accounting for its anti-cancer properties. Through this mechanism, WP1130 has been shown to downregulate the antiapoptotic proteins Bcr/Abl and Jak2 and to upregulate the proapoptotic proteins MCL-1 and p53. WP1130-induced apoptosis and anti-proliferation in tumor cells have been implicated in the treatment of chronic myelogenous leukemia (CML), melanoma, glioblastoma and myeloproliferative disorders. It has also been shown to inhibit autophagy. WP1130 exhibits antiviral activity through activation of the unfolded protein response (UPR) and is an antibacterial compound against S. aureus including clinically isolated MRSA strains. WP1130 inhibits the LPS/ATP-induced deubiquitination of NLRP3 and further increases NLRP3 ubiquitination. This leads to inhibition of NLRP3 activation, indicating that deubiquitination of NLRP3 by the priming and activation signals is critical for its activation.