Proteolysis Targeting Chimeras for the Selective Degradation of Mcl-1/Bcl-2 Derived from Nonselective Target Binding Ligands

Wang, Ziqian; He, Nianzhe; Guo, Zongwei; Niu, Cuili; Song, Ting; Guo, Yafei; Cao, Kai; Wang, Anhui; Zhu, Junjie; Zhang, Xiaodong; Zhang, Zhichao

doi:10.1021/acs.jmedchem.9b00919

Cited by 89 publications

(67 citation statements)

References 45 publications

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“…In such scenarios, the ability to inhibit MCL1 in a tissue or disease specific manner rather than systemically would be highly valuable. Harnessing protein degradation pathways, such as with PROTAC small molecules, is one way to achieve such contextual inhibition [63], and this is indeed a strategy being pursued for MCL1 [64,65]. Distinct from PROTACs, compounds that act as "molecular glues" to enhance the activity of a cognate E3 ligase on its substrate have also recently been described [66].…”

Section: Discussionmentioning

confidence: 99%

MARCH5 requires MTCH2 to coordinate proteasomal turnover of the MCL1:NOXA complex

et al. 2020

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MCL1, a BCL2 relative, is critical for the survival of many cells. Its turnover is often tightly controlled through both ubiquitin-dependent and-independent mechanisms of proteasomal degradation. Several cell stress signals, including DNA damage and cell cycle arrest, are known to elicit distinct E3 ligases to ubiquitinate and degrade MCL1. Another trigger that drives MCL1 degradation is engagement by NOXA, one of its BH3-only protein ligands, but the mechanism responsible has remained unclear. From an unbiased genome-wide CRISPR-Cas9 screen, we discovered that the ubiquitin E3 ligase MARCH5, the ubiquitin E2 conjugating enzyme UBE2K, and the mitochondrial outer membrane protein MTCH2 cooperate to mark MCL1 for degradation by the proteasome-specifically when MCL1 is engaged by NOXA. This mechanism of degradation also required the MCL1 transmembrane domain and distinct MCL1 lysine residues to proceed, suggesting that the components likely act on the MCL1:NOXA complex by associating with it in a specific orientation within the mitochondrial outer membrane. MTCH2 has not previously been reported to regulate protein stability, but is known to influence the mitochondrial localization of certain key apoptosis regulators and to impact metabolism. We have now pinpointed an essential but previously unappreciated role for MTCH2 in turnover of the MCL1:NOXA complex by MARCH5, further strengthening its links to BCL2-regulated apoptosis.

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Section: Discussionmentioning

confidence: 99%

MARCH5 requires MTCH2 to coordinate proteasomal turnover of the MCL1:NOXA complex

et al. 2020

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“…As mentioned above, MCL1 interacted with BCL2. Therefore, Zhang and coworkers also realized the degradation of MCL1 by PROTAC C1 with a DC 50 value of 0.7 µM and achieved degradation of BCL2 at the same time 128 (Fig. 29).…”

Section: Mcl1mentioning

confidence: 90%

“…The first BCL2 degrade was reported by Zhang and coworkers in 2019. the designed PROTACs for α-helix-mediated PPI targets to degrade BCL2 128 (Fig. 8).…”

Section: Bcl2mentioning

confidence: 99%

PROTACs: great opportunities for academia and industry

Sun

Gao

Yang

et al. 2019

Sig Transduct Target Ther

451

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Although many kinds of therapies are applied in the clinic, drug-resistance is a major and unavoidable problem. Another disturbing statistic is the limited number of drug targets, which are presently only 20-25% of all protein targets that are currently being studied. Moreover, the focus of current explorations of targets are their enzymatic functions, which ignores the functions from their scaffold moiety. As a promising and appealing technology, PROteolysis TArgeting Chimeras (PROTACs) have attracted great attention both from academia and industry for finding available approaches to solve the above problems. PROTACs regulate protein function by degrading target proteins instead of inhibiting them, providing more sensitivity to drug-resistant targets and a greater chance to affect the nonenzymatic functions. PROTACs have been proven to show better selectivity compared to classic inhibitors. PROTACs can be described as a chemical knockdown approach with rapidity and reversibility, which presents new and different biology compared to other gene editing tools by avoiding misinterpretations that arise from potential genetic compensation and/or spontaneous mutations. PRTOACs have been widely explored throughout the world and have outperformed not only in cancer diseases, but also in immune disorders, viral infections and neurodegenerative diseases. Although PROTACs present a very promising and powerful approach for crossing the hurdles of present drug discovery and tool development in biology, more efforts are needed to gain to get deeper insight into the efficacy and safety of PROTACs in the clinic. More target binders and more E3 ligases applicable for developing PROTACs are waiting for exploration.

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“…Similar strategies could also be employed to reduce the potential on-target cardiac toxicity associated with MCL-1 inhibition. MCL-1 PROTACs have been recently developed [19,20]. It will be interesting to evaluate whether these degraders have the benefit of reduced on-target toxicity.…”

Section: Future Perspectivementioning

confidence: 99%