Discovery and structure-activity relationship studies of N-substituted indole derivatives as novel Mcl-1 inhibitors

Luan, Shenglin; Ge, Qi; Chen, Yedong; Dai, Mingyang; Yang, Jinyu; Li, Kun; Liu, Dan; Zhao, Liang

doi:10.1016/j.bmcl.2017.03.028

Cited by 14 publications

(2 citation statements)

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“…This strategy effectively reduced the number of rotatable conformations in the molecule, resulting in an Mcl-1 inhibitor with improved affinity . Our group conducted a fluorescence polarization assay (FPA) on a small in-house compound library and obtained molecules with moderate inhibitory activity against Mcl-1 through molecular docking experiments. , Zhang et al implemented a fragment-based drug design strategy by modifying the hydrophobic region of the molecule that extends toward the P2 pocket and synthesizing 1-substituted indole-2-carboxylic acid as a selective Mcl-1 inhibitor . Fang et al connected acylsulfonamide structures through carbon atom linkage based on the structure of indole scaffolds and obtained molecules with submicromolar in vitro inhibitory activity against Mcl-1. , These molecules enrich the application of indole scaffolds in Mcl-1 inhibitors discovery and help to gain the understanding of the binding characteristics of indole scaffolds with Mcl-1 (Figure ).…”

Section: Research Progress Of Modulators Targeting Mcl-1 In Cancer Tr...mentioning

confidence: 99%

Targeting Myeloid Leukemia-1 in Cancer Therapy: Advances and Directions

Deng,

Han,

Liu

et al. 2024

J. Med. Chem.

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As a tripartite cell death switch, B-cell lymphoma protein 2 (Bcl-2) family members precisely regulate the endogenous apoptosis pathway in response to various cell signal stresses through protein− protein interactions. Myeloid leukemia-1 (Mcl-1), a key anti-apoptotic Bcl-2 family member, is positioned downstream in the endogenous apoptotic pathway and plays a central role in regulating mitochondrial function. Mcl-1 is highly expressed in a variety of hematological malignancies and solid tumors, contributing to tumorigenesis, poor prognosis, and chemoresistance, making it an attractive target for cancer treatment. This Perspective aims to discuss the mechanism by which Mcl-1 regulates apoptosis and non-apoptotic functions in cancer cells and to outline the discovery and optimization process of potent Mcl-1 modulators. In addition, we summarize the structural characteristics of potent inhibitors that bind to Mcl-1 through multiple co-crystal structures and analyze the cardiotoxicity caused by current Mcl-1 inhibitors, providing prospects for rational targeting of Mcl-1. ■ SIGNIFICANCE • Pharmacological inhibition of protein−protein interactions between Mcl-1 and its substrates has become a promising approach to induce apoptotic or nonapoptotic functions in the treatment of various diseases. • Recent advancements in targeting Mcl-1 for tumor therapy are systematically summarized from medicinal chemistry insights. • The structural characteristics of potent inhibitors binding with Mcl-1 are analyzed. • The cardiotoxicity of Mcl-1 inhibitors is discussed, and structural modification strategies for future Mcl-1 inhibitors development are proposed.

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Section: Research Progress Of Modulators Targeting Mcl-1 In Cancer Tr...mentioning

confidence: 99%

Targeting Myeloid Leukemia-1 in Cancer Therapy: Advances and Directions

Deng,

Han,

Liu

et al. 2024

J. Med. Chem.

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“…Several studies have been reported on novel peptides [19][20][21] and non-peptide leads [22][23][24][25][26][27] with activity values in the subnanomolar range, but none have reached the market. In recent years, researchers have identified few selective Mcl1 inhibitors that showed significant downregulating effects.…”

Section: Introductionmentioning

confidence: 99%

Investigating the Molecular Basis of N-Substituted 1-Hydroxy-4-Sulfamoyl-2-Naphthoate Compounds Binding to Mcl1

2019

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Myeloid cell leukemia-1 (Mcl1) is an anti–apoptotic protein that has gained considerable attention due to its overexpression activity prevents cell death. Therefore, a potential inhibitor that specifically targets Mcl1 with higher binding affinity is necessary. Recently, a series of N-substituted 1-hydroxy-4-sulfamoyl-2-naphthoate compounds was reported that targets Mcl1, but its binding mechanism remains unexplored. Here, we attempted to explore the molecular mechanism of binding to Mcl1 using advanced computational approaches: pharmacophore-based 3D-QSAR, docking, and MD simulation. The selected pharmacophore—NNRRR—yielded a statistically significant 3D-QSAR model containing high confidence scores (R2 = 0.9209, Q2 = 0.8459, and RMSE = 0.3473). The contour maps—comprising hydrogen bond donor, hydrophobic, negative ionic and electron withdrawal effects—from our 3D-QSAR model identified the favorable regions crucial for maximum activity. Furthermore, the external validation of the selected model using enrichment and decoys analysis reveals a high predictive power. Also, the screening capacity of the selected model had scores of 0.94, 0.90, and 8.26 from ROC, AUC, and RIE analysis, respectively. The molecular docking of the highly active compound—C40; 4-(N-benzyl-N-(4-(4-chloro-3,5-dimethylphenoxy) phenyl) sulfamoyl)-1-hydroxy-2-naphthoate—predicted the low-energy conformational pose, and the MD simulation revealed crucial details responsible for the molecular mechanism of binding with Mcl1.

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