Hot-Spots of Mcl-1 Protein

Denis, Camille; Santos, Jana Sopková−de Oliveira; Bureau, Ronan; Voisin‐Chiret, Anne Sophie

doi:10.1021/acs.jmedchem.9b00983

Cited by 59 publications

(51 citation statements)

References 100 publications

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“…Anti-apoptotic family members including MCL-1 form a hydrophobic groove (composed of BH1-BH3 domains), where four hydrophobic binding pockets (P1–P4) guide the interaction with hydrophobic residues (h1-h4) of BH3 domains. In addition, a conserved arginine within the BH1 domain is a key binding anchor for a conserved aspartate of BH3-only proteins [ 10 – 12 ].…”

Section: Multi-functional Roles Of Mcl-1mentioning

confidence: 99%

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

et al. 2020

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Cell death escape is one of the most prominent features of tumor cells and closely linked to the dysregulation of members of the Bcl-2 family of proteins. Among those, the anti-apoptotic family member myeloid cell leukemia-1 (MCL-1) acts as a master regulator of apoptosis in various human malignancies. Irrespective of its unfavorable structure profile, independent research efforts recently led to the generation of highly potent MCL-1 inhibitors that are currently evaluated in clinical trials. This offers new perspectives to target a so far undruggable cancer cell dependency. However, a detailed understanding about the tumor and tissue type specific implications of MCL-1 are a prerequisite for the optimal (i.e., precision medicine guided) use of this novel drug class. In this review, we summarize the major functions of MCL-1 with a special focus on cancer, provide insights into its different roles in solid vs. hematological tumors and give an update about the (pre)clinical development program of state-of-the-art MCL-1 targeting compounds. We aim to raise the awareness about the heterogeneous role of MCL-1 as drug target between, but also within tumor entities and to highlight the importance of rationale treatment decisions on a case by case basis.

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Section: Multi-functional Roles Of Mcl-1mentioning

confidence: 99%

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

et al. 2020

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“…We observed that addition of the peptide induced significant CSP primarily localized to the BH3-binding groove of MCL1 corresponding to the three hydrophobic pockets that mediate BH3 binding (homologous rBH3 residues H2, H3, and H4 in Table 1 )—p2, p3, and p4. Amongst these, amino acids required for hydrophobic interactions, including the L267 of the p2 pocket, F228 of the p3 pocket, and the V265 of the p4 pocket, were all significantly perturbed 30 , 31 . There were also several amino acids in which the corresponding peaks had line broadening beyond detection (red in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Amongst these, R263 is the most significant as it mediates a critical stabilizing salt bridge with the conserved acidic amino acid within the BH3 or rBH3 helices 31 (Table 1 ). Additionally, V243 of the p2 pocket and V216 and V220 of the p4 pocket could no longer be detected 31 . Of note, R263 and the hydrophobic pockets p2 and p3, are core interaction sites for the emerging MCL1-specific BH3 mimetics 30 , 32 .…”

Section: Resultsmentioning

confidence: 99%

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MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

et al. 2020

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MCL1, an anti-apoptotic protein that controls chemosensitivity and cell fate through its regulation of intrinsic apoptosis, has been identified as a high-impact target in anti-cancer therapeutic development. With MCL1-specific inhibitors currently in clinical trials, it is imperative that we understand the roles that MCL1 plays in cells, especially when targeting the Bcl-2 homology 3 (BH3) pocket, the central region of MCL1 that mediates apoptotic regulation. Here, we establish that MCL1 has a direct role in controlling p73 transcriptional activity, which modulates target genes associated with DNA damage response, apoptosis, and cell cycle progression. This interaction is mediated through the reverse BH3 (rBH3) motif in the p73 tetramerization domain, which restricts p73 assembly on DNA. Here, we provide a novel mechanism for protein-level regulation of p73 transcriptional activity by MCL1, while also framing a foundation for studying MCL1 inhibitors in combination with platinum-based chemotherapeutics. More broadly, this work expands the role of Bcl-2 family signaling beyond cell fate regulation.

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“…However, SAR and docking results have shown that the two derivatives did not completely occupy the p2 pocket, which is one of the deepest pockets of Bcl‐2 and Mcl‐1. Moreover, the p1 and the p2 pocket are adjacent without much steric hindrance, [ 29,30 ] rendering more space for the substituents at R 1 ‐position (Figure S1). Therefore, we designed and synthesized the B series compounds (Figure 1) that have an additional benzene ring at R 1 ‐position with larger volume, more rigid structure, and more hydrophobic nature than the previous optimization on the basis of the thiomorpholine and maybe occupy the p2 and p1 hydrophobic pockets completely.…”

Section: Resultsmentioning

confidence: 99%

Structure‐based design, synthesis, and evaluation of Bcl‐2/Mcl‐1 dual inhibitors

Zhu

Wang

Guo

et al. 2020

Archiv der Pharmazie

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Based on our previously reported Bcl-2/Mcl-1 dual inhibitor 4-thiomorpholinyl-2-cyano-3-amidinophenalenone (A1) that simultaneously occupies the p2 and p4 hydrophobic pockets of Bcl-2 and Mcl-1, we optimized molecules with different bond angles of the groups extending to the p4 pocket and bulky hydrophobic groups to explore p2. Research on structure-activity relationship resulted in a new derivative B4 that is capable of occupying both the p2 and p4 more deeply and completely than A1, with K i values determined by fluorescence polarization assay (FPAs) improving to 0.31 μM for Bcl-2 and 0.16 μM for Mcl-1. Furthermore, B4 exhibited selective lethality on cancer cells over normal cells. It showed stronger apoptosis induction than (-)-gossypol on a Bcl-2/Mcl-1-dependent cancer cell line and killed an Mcl-1-dependent cell line which is resistant to ABT-199 treatment. K E Y W O R D S anticancer activities, apoptosis, Bcl-2/Mcl-1 dual inhibitor

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Hot-Spots of Mcl-1 Protein

Cited by 59 publications

References 100 publications

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

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

MCL1 binds and negatively regulates the transcriptional function of tumor suppressor p73

Structure‐based design, synthesis, and evaluation of Bcl‐2/Mcl‐1 dual inhibitors

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