Figure 1. Mechanisms of MCL-1 inhibitor-induced MCL-1 protein upregulation, stability, and induction of apoptosis.

Three major pathways (A–C) have been demonstrated for upregulation of MCL-1 protein after treatment with MCL-1 inhibitors. (A) The MCL-1 protein stability is facilitated in part following binding with the MCL-1 inhibitors leading to a conformational change in the protein that enhance MCL-1^Thr163 phosphorylation by upstream MEK/ERK signaling pathway. (B) MCL-1 inhibitors treatment enhanced DUB activity and induced Noxa dissociation from MCL-1, followed by rapid Noxa degradation leading to MCL-1 stability through potentiating USP9x: MCL-1 interaction. Additionally, MCL-1 inhibitors reduce the levels of the E3 ligase Mule, resulting in defective ubiquitination of MCL-1. The net effect is seen in an increased stability of the MCL-1 protein. (C) MCL-1 inhibitor binding to MCL-1 protein induces MCL-1 dissociation from BAX/BAK pro-apoptotic protein complex, facilitating their oligomerization resulting in induction of apoptosis. Black arrows indicate potentiating effect, red arrows indicate inhibitory effect. X marks indicate disruption of the normal pathway.