Overview of WP1130 activity in CML cells. (Top left) Bcr-Abl is ubiquitinated with K63-linked ubiquitin polymers, but balanced E3 ligase and DUB activities prevent its accumulation and detection. WP1130 prevents deubiquitination of Bcr-Abl (or increases E3 ligase activity), resulting in detectable ubiquitination of Bcr-Abl and its trafficking to the aggresome. (Top right) Mcl-1 undergoes balanced ubiquitination and deubiquitination to regulate its stability and entry into the proteasome. WP1130 inhibits Usp9x activity, resulting in increased Mcl-1 ubiquitination and degradation by the proteasome. (Bottom left) In CML cells, Bcr-Abl phosphorylates multiple substrates, leading to transformation and increased expression of Mcl-1 and other anti-apoptotic proteins. Balanced ubiquitination/deubiquitination reactions result in steady-state protein levels. (Bottom right) WP1130 increases Bcr-Abl ubiquitination, resulting in its translocation to the aggresome, where it is unable to maintain signal transduction and gene expression. WP1130 directly inhibits Usp9x activity, resulting in the ubiquitination and proteasomal destruction of Mcl-1. Loss of Bcr-Abl signaling and Mcl-1 apoptotic protection results in CML cell apoptosis.