Allosteric inhibition of antiapoptotic MCL-1

Lee, Susan; Wales, Thomas E.; Escudero, Silvia; Cohen, D. Walter; Luccarelli, James; Gallagher, Catherine G; Cohen, Nicole A.; Huhn, Annissa J.; Bird, Gregory H.; Engen, John R.; Walensky, Loren D.

doi:10.1038/nsmb.3223

Cited by 50 publications

(69 citation statements)

References 52 publications

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“…Allostery has emerged as a key feature of BCL-2 family protein regulation, influencing both the apoptotic response and opportunities to pharmacologically manipulate it. For example, BH3-only triggering of BAX at the α1/α6 interaction site on the N-terminal face of the protein drives release of α9 at the C-terminal face for mitochondrial translocation 5 , 46 , BCL-2 BH4 and vMIA engagement restrict the conformational activation of BAX 7 , 8 , PUMA induces partial unfolding of BCL-X L to release sequestered p53 from a distal site 47 , and covalent modification or mutagenesis of an α6 cysteine of MCL-1 influences the functional activity of its canonical anti-apoptotic binding pocket at the opposite face of the protein 48 . Indeed, one of the cardinal features and mechanistic requirements for activation and homo-oligomerization of the essential executioner proteins of mitochondrial apoptosis, BAX and BAK, involves exposure of their respective BH3 domains, which can either be trapped by the canonical pockets of anti-apoptotic members 12 or remain free to mediate formation of toxic mitochondrial pores 27 .…”

Section: Discussionmentioning

confidence: 99%

Allosteric sensitization of proapoptotic BAX

et al. 2017

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BAX is a critical apoptotic regulator that can be transformed from a cytosolic monomer into a lethal mitochondrial oligomer, yet drug strategies to modulate it are underdeveloped due to longstanding difficulties in conducting screens on this aggregation-prone protein. Here, we overcame prior challenges and performed an NMR-based fragment screen of full-length human BAX. We identified a compound that sensitizes BAX activation by binding to a pocket formed by the junction of the α3/α4 and α5/α6 hairpins. Biochemical and structural analyses revealed that the molecule sensitizes BAX by allosterically mobilizing the α1–α2 loop and BAX BH3 helix, two motifs implicated in the activation and oligomerization of BAX, respectively. By engaging a region of core hydrophobic interactions that otherwise preserve the BAX inactive state, the identified compound informs fundamental mechanisms for conformational regulation of BAX and provides a new opportunity to reduce the apoptotic threshold for potential therapeutic benefit.

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Section: Discussionmentioning

confidence: 99%

Allosteric sensitization of proapoptotic BAX

et al. 2017

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“…Lee et al . identified a small molecule to covalently bind to MCL-1 Cys286, which is both unique to MCL-1 and distant from the canonical binding groove [50]. The compound induced conformational changes and the allosteric inhibition of BH3-domain interaction with MCL-1.…”

Section: Non-canonical Targeting Of Anti-apoptotic Bcl-2 Proteinsmentioning

confidence: 99%

Progress in targeting the BCL-2 family of proteins

Garner

López

Reyna

et al. 2017

Current Opinion in Chemical Biology

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The network of protein-protein interactions among the BCL-2 protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Anti-apoptotic BCL-2 proteins are considered promising targets for drug discovery and exciting clinical progress has stimulated intense investigations in the broader family. Here, we discuss recent developments in small molecules targeting anti-apoptotic proteins and alternative approaches to targeting BCL-2 family interactions. These studies advance our understanding of the role of BCL-2 family proteins in physiology and disease, providing unique tools for dissecting these functions. The BCL-2 family of proteins is a prime example of targeting protein-protein interactions and further chemical biology approaches will increase opportunities for novel targeted therapies in cancer, autoimmune and aging-associated diseases.

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“…Additional MCL1 inhibitors are being developed by other companies, notably AMG 176 which is in Phase 1 for MM (http://www.amgenpipeline.com/pipeline/) and optimization of A-1210477 [107] can also be expected. Another novel development is engineering of covalent compounds that target the MCL1 BH3 groove and/or other reactive cysteine or lysine residues [113,114]. While a detailed description and comparison of the data obtained with these novel MCL1 inhibitors is beyond the scope of this review, it seems clear that covalent targeting may greatly enhance specificity.…”

Section: Bcl-2 Members As Therapeutic Target -Bh3 Mimetics and Beyondmentioning

confidence: 99%

Exploiting the pro-apoptotic function of NOXA as a therapeutic modality in cancer

Guikema

Amiot

Eldering

2017

Expert Opinion on Therapeutic Targets

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Direct targeting of Bcl-2 members for therapeutic purposes in cancer has become a clinical reality with the FDA approval of ABT-199/Venetoclax. Other highly specific BH3-mimetics are in pre-clinical development. Understanding the functional interactions among the Bcl-2 family is of prime importance to fully exploit their potential. NOXA is considered a rather weak BH3-only member but it has unexplored potential in various settings, which are of relevance in cancer. NOXA is best known as a selective inhibitor of MCL1, itself overexpressed in many cancers, and this protein pair forms an important rheostat in many forms of cell stress. Areas covered: We summarize the distinct pathways that induce NOXA RNA and protein, and how this may be exploited in solid and hematopoietic cancers, with a focus on multiple myeloma and chronic lymphocytic leukemia. Expert opinion: The therapeutic potential to induce NOXA is not yet fully explored nor exploited, and we suggest 1) areas that require further fundamental investigation, including replicative stress and epigenetics, 2) areas where translation to therapeutic application seems more imminent (ER stress, ROS, inhibition of NOXA degradation) 3) a complementary approach to inducing NOXA by direct targeting of MCL1 via the novel BH3 mimetic S63845 and similar compounds.

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Allosteric inhibition of antiapoptotic MCL-1

Cited by 50 publications

References 52 publications

Allosteric sensitization of proapoptotic BAX

Allosteric sensitization of proapoptotic BAX

Progress in targeting the BCL-2 family of proteins

Exploiting the pro-apoptotic function of NOXA as a therapeutic modality in cancer

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