Development of a series of novel Mcl-1 inhibitors bearing an indole carboxylic acid moiety

Deng, Hongguang; Huang, Min; Liu, Hui; Zhang, Hong; Liu, Liang; Gao, Bensheng; Li, Xianlu; Li, Jinbo; Niu, Qun; Zhang, Zhenwei; Luan, Shenglin; Zhang, Jingyi; Jing, Yongkui; Liú, Dan; Zhao, Liang

doi:10.1016/j.bioorg.2022.106018

Cited by 3 publications

(1 citation statement)

References 34 publications

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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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Mitochondria Localized Anticancer Iridium(III) Prodrugs for Targeted Delivery of Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors and Cytotoxic Iridium(III) Complex

Dixit,

Negi,

Venkatesh

2024

Inorg. Chem.

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Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic oncoprotein overexpressed in several malignancies and acts as one of the promising therapeutic targets for cancer. Even though there are several small molecule based Mcl-1 inhibitors reported, the delivery of Mcl-1 inhibitor at the target site is quite challenging. In this regard, we developed a series of mitochondria targeting luminescent cyclometalated iridium(III) prodrugs bearing Mcl-1 inhibitors via ester linkage due to the presence of Mcl-1 protein in the outer mitochondrial membrane. Among the synthesized prodrugs, IrThpy@L2 was found to exhibit the potent cytotoxicity (IC 50 = 30.93 nM) against HCT116 cell line when compared with bare Mcl-1 inhibitors (IC 50 > 100 μM). Mechanistic studies further revealed that IrThpy@L2 quickly gets internalized inside the mitochondria of HCT116 cells and undergoes activation in the presence of overexpressed esterase which leads to the release of two cytotoxic species i.e. Mcl-1 inhibitors (I-2) and cytotoxic iridium(III) complex (IrThpy@OH). The improved cytotoxicity of IrThpy@L2 is due to the mitochondria targeting ability of iridium(III) prodrug, subsequent esterase activated release of I-2 to inhibit Mcl-1 protein and IrThpy@OH to generate reactive oxygen species (ROS). After prodrug activation, the released cytotoxic species cause mitochondrial membrane depolarization, activate a cascade of mitochondria-mediated cell death events, and arrest the cell cycle in S-phase which leads to apoptosis. The potent anticancer activity of IrThpy@L2 was further evident from the drastic morphological changes, size reduction in the solid tumor mimicking 3D multicellular tumor spheroids (MCTS) of HCT116.

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Indole Derivatives: A Versatile Scaffold in Modern Drug Discovery—An Updated Review on Their Multifaceted Therapeutic Applications (2020–2024)

Mo,

Rao,

Kaur

et al. 2024

Molecules

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Indole derivatives have become an important class of compounds in medicinal chemistry, recognized for their wide-ranging biological activities and therapeutic potential. This review provides a comprehensive overview of recent advances in the evaluation of indole-based compounds in the last five years, highlighting their roles in cancer treatment, infectious disease management, anti-inflammatory therapies, metabolic disorder interventions, and neurodegenerative disease management. Indole derivatives have shown significant efficacy in targeting diverse biological pathways, making them valuable scaffolds in designing new drugs. Notably, these compounds have demonstrated the ability to combat drug-resistant cancer cells and pathogens, a significant breakthrough in the field, and offer promising therapeutic options for chronic diseases such as diabetes and hypertension. By summarizing recent key findings and exploring the underlying biological mechanisms, this review underscores the potential of indole derivatives in addressing major healthcare challenges, thereby instilling hope and optimism in the field of modern medicine.

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Development of a series of novel Mcl-1 inhibitors bearing an indole carboxylic acid moiety

Cited by 3 publications

References 34 publications

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

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

Mitochondria Localized Anticancer Iridium(III) Prodrugs for Targeted Delivery of Myeloid Cell Leukemia-1 (Mcl-1) Inhibitors and Cytotoxic Iridium(III) Complex

Indole Derivatives: A Versatile Scaffold in Modern Drug Discovery—An Updated Review on Their Multifaceted Therapeutic Applications (2020–2024)

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