Discovery of Novel, Potent, and Selective Small-Molecule Menin–Mixed Lineage Leukemia Interaction Inhibitors through Attempting Introduction of Hydrophilic Groups

Lei, Hao; Zhang, San‐Qi; Bai, Huanrong; Zhao, Hongshan; Sun, Jiajia; Chuai, Hongyan; Xin, Minhang

doi:10.1021/acs.jmedchem.2c01313

Cited by 6 publications

(5 citation statements)

References 38 publications

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“…Recent extensive drug development focused on the Menin-MLL interaction [ 30 , 44 , 49 ] also suggests Menin's broad orchestration roles in deploying metabolic pathways, especially the Menin’s deploying model on FoxO1/PPARγ/SIRT1 would contribute to the drug discovery on the MAFLD. This coincides with the latest proposal that the American Diabetes Association guidelines in 2022 have proposed PPARγ agonists (pioglitazone) and glucagon-like peptide-1 (GLP1) receptor agonists for treating diabetes, NAFLD, or NASH [ 16 , 29 ], in response to global health threats, possibily because Menin/SIRT1 mediated PPARγ acetylation plays a crucial role in orchestrating adipose plasticity and metabolic rhythms [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

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Menin orchestrates hepatic glucose and fatty acid uptake via deploying the cellular translocation of SIRT1 and PPARγ

Liu,

Li,

Sun

et al. 2023

Cell Biosci

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Background Menin is a scaffold protein encoded by the Men1 gene, which interacts with various transcriptional proteins to activate or repress cellular processes and is a key mediator in multiple organs. Both liver-specific and hepatocyte-specific Menin deficiency promotes high-fat diet-induced liver steatosis in mice, as well as insulin resistance and type 2 diabetic phenotype. The potential link between Menin and hepatic metabolism homeostasis may provide new insights into the mechanism of fatty liver disease. Results Disturbance of hepatic Menin expression impacts metabolic pathways associated with non-alcoholic fatty liver disease (NAFLD), including the FoxO signaling pathway, which is similar to that observed in both oleic acid-induced fatty hepatocytes model and biopsied fatty liver tissues, but with elevated hepatic Menin expression and inhibited FABP1. Higher levels of Menin facilitate glucose uptake while restraining fatty acid uptake. Menin targets the expression of FABP3/4/5 and also CD36 or GK, PCK by binding to their promoter regions, while recruiting and deploying the cellular localization of PPARγ and SIRT1 in the nucleus and cytoplasm. Accordingly, Menin binds to PPARγ and/or FoxO1 in hepatocytes, and orchestrates hepatic glucose and fatty acid uptake by recruiting SIRT1. Conclusion Menin plays an orchestration role as a transcriptional activator and/or repressor to target downstream gene expression levels involved in hepatic energy uptake by interacting with the cellular energy sensor SIRT1, PPARγ, and/or FoxO1 and deploying their translocations between the cytoplasm and nucleus, thereby maintaining metabolic homeostasis. These findings provide more evidence suggesting Menin could be targeted for the treatment of hepatic steatosis, NAFLD or metabolic dysfunction-associated fatty liver disease (MAFLD), and even other hepatic diseases. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

“…Nowadays, the Menin-MLL (mixed lineage leukemia) interaction is regarded as a potential therapeutic strategy for leukemia and cancers. Many novel, potent, selective small molecules focused on the interaction have been discovered [ 30 , 35 , 44 , 49 ].…”

Section: Introductionmentioning

confidence: 99%

Menin orchestrates hepatic glucose and fatty acid uptake via deploying the cellular translocation of SIRT1 and PPARγ

Liu,

Li,

Sun

et al. 2023

Cell Biosci

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“…[107] Mechanistically, inhibition of NAE could lead to the Pyrido [3,2-d]pyrimidine-sulfone hybrid 95 (C20, IC 50 : 300 nM, MTT assay) exhibited profound antiproliferative activity against MV4-11 cells harboring an MLL fusion protein. [108] Mechanistically, C20 reversed the differentiation arrest, caused significant cell-cycle arrest at the G0/G1 phase, and induced apoptosis. 2.19, 1.50 and 1.23 µM, SRB assay) against K562, HL-60 and MOLM-13 myeloid leukemia cell lines.…”

Section: Purine Derivativesmentioning

confidence: 97%

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

Xu,

Wang,

2024

Archiv der Pharmazie

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Cancer, characterized by uncontrolled cell growth and metastasis, is responsible for nearly one in six deaths and represents a severe threat to public health worldwide. Chemotherapy can substantially improve the quality of life and survival of patients with cancer, but anticancer chemotherapeutics are associated with a range of adverse effects. Moreover, almost all currently available anticancer chemotherapeutics could develop drug resistance over a period of time of application in cancer patients and ultimately lead to cancer relapse and death in 90% of patients, creating an urgent need to develop new anticancer agents. Fused pyrimidines trait the inextricable part of DNA and RNA and are vital in numerous biological processes. Fused pyrimidines can act on various biological cancer targets and have the potential to address drug resistance. In addition, more than 20 fused pyrimidines have already been approved for clinical treatment of different cancers and occupy a prominent place in the current therapeutic arsenal, revealing that fused pyrimidines are privileged scaffolds for the development of novel anticancer chemotherapeutics. The purpose of this review is to summarize the current scenario of fused pyrimidines with in vivo anticancer therapeutic potential along with their acute toxicity, metabolic profiles as well as pharmacokinetic properties, toxicity and mechanisms of action developed from 2020 to the present to facilitate further rational exploitation of more effective candidates.

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“…Abnormal blood cell counts and a rise in the number of immature blood cells in circulation are the commonalities among them all. [10] The worldwide scenario about leukemia is alarming. Leukemia occurs in various forms, including acute lymphocytic leukemia (ALL), Chronic lymphocytic leukemia (CLL), Acute myeloid leukemia (AML), and Chronic myeloid leukemia (CML) together putting a death toll of 3.9 % worldwide in 2023.…”

Section: Introductionmentioning

confidence: 99%

“…Depending on which organs are affected, leukemia can present with a variety of symptoms. Abnormal blood cell counts and a rise in the number of immature blood cells in circulation are the commonalities among them all [10] …”

Section: Introductionmentioning

confidence: 99%

Thiazole as an Indispensable Scaffold in Anti‐Leukemic Agents: A Semicentennial Review

Sharma,

Das,

Jadhav

et al. 2024

ChemistrySelect

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Leukemia affects the body‘s blood‐forming tissues, especially the bone marrow and lymphatic system. Leukemia incidence varies between communities and between pathological kinds. Many treatment modalities exist for leukemia, such as chemotherapy, targeted therapy, radiation therapy, bone marrow transplantation, immunotherapy, and the engineering of immune cells to fight leukemia. Leukemia might be treated with a variety of pharmaceuticals, the most popular of which are imatinib (Gleevec), dasatinib (Sprycel), nilotinib (Tasigna), obinutuzumab (Gazyva), venetoclax (Venclexta), and so on. Thiazole is one of the scaffolds that are actively explored in leukemia. Derivatives having the thiazole nucleus have been surfacing as potent candidates in the treatment of leukemia for quite sometime now, but a consolidated report accumulating all these ventures is absent. Numerous naturally occurring substances, including flavones, alkaloids, anabolic steroids, and vitamin B1 (thiamine), include the basic thiazole molecule. Thiazole derivatives have been researched for their possible therapeutic effects in the treatment of leukemia. Thus, this review comprising reports regarding the effect of different thiazole‐based species in leukemia is a timely effort to the best of our knowledge. This review covers the chronological development of antileukemic thiazole‐based molecules, their synthesis, biological activity, and structure–activity relationships.

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Discovery of Novel, Potent, and Selective Small-Molecule Menin–Mixed Lineage Leukemia Interaction Inhibitors through Attempting Introduction of Hydrophilic Groups

Cited by 6 publications

References 38 publications

Menin orchestrates hepatic glucose and fatty acid uptake via deploying the cellular translocation of SIRT1 and PPARγ

Menin orchestrates hepatic glucose and fatty acid uptake via deploying the cellular translocation of SIRT1 and PPARγ

Current scenario of fused pyrimidines with in vivo anticancer therapeutic potential

Thiazole as an Indispensable Scaffold in Anti‐Leukemic Agents: A Semicentennial Review

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