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Fig. 3 | Journal of Hematology & Oncology

Fig. 3

From: MCL-1 inhibitors, fast-lane development of a new class of anti-cancer agents

Fig. 3

Direct and indirect targeting of MCL-1. (a) There are two principal approaches in the targeting of MCL-1: indirect inhibition through inhibition of transcription or translation and downregulation of MCL-1 via targeting of proteasomal degradation and direct inhibition through interruption of protein–protein interactions via small molecule inhibitors (BH3-mimetics). (b) At the mitochondrial membrane, MCL-1 binds the proapoptotic multidomain effector BAK to prevent cell death. In primed cells, there is only a minimal excess of anti- over pro-apoptotic proteins. A variety of cell stressors increase the expression of the proapoptotic sensors, including the BH3-only proteins (i.e., BIM, BID, PUMA, NOXA and BAD). The treatment with an MCL-1 inhibitor will liberate BAK from binding to MCL-1. BAK will oligomerize and form pores in the mitochondrial membrane leading to cytochrome c release into the cytosol and activation of the caspase cascade. (c) MCL-1 can be phosphorylated by several protein kinases which enables the recognition of MCL-1 by its E3 ubiquitin-ligases TrCP or FBW7. In addition, the E3 ubiquitin-ligase Mule can interact either with the C- or N-terminus of MCL-1 in a phosphorylation-independent manner. This binding can be inhibited by BIM and PUMA or increased by NOXA. Ubiquitination of MCL-1 targets it for proteasomal degradation. It can be opposed by the deubiquitinases such as USP9X that directly removes polyubiquitin chains, which results in MCL‑1 stabilization

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