Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia

Guo, Zhaodi; Zhang, Zhuqing; Yang, Hong; Cao, Danyan; Xu, Xiaowei; Zheng, Xingling; Chen, Danqi; Wang, Qi; Li, Yanlian; Li, Jian; Du, Zhimin; Wang, Xin; Chen, Lin; Ding, Jian; Shen, Jingkang; Geng, Meiyu; Huang, Xun; Xiong, Bing

doi:10.1021/acs.jmedchem.9b00297

Cited by 17 publications

(19 citation statements)

References 47 publications

(167 reference statements)

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“… 102 Therefore, PRMT4 is considered an appealing therapeutic target for anticancer drug development, and in fact a few inhibitors have been developed with different degrees of potency and selectivity. 24 , 41 , 52 , 103 …”

Section: Resultsmentioning

confidence: 99%

Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction–Reconstruction and Fragment-Growing Approach

et al. 2022

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Protein arginine methyltransferases (PRMTs) are important therapeutic targets, playing a crucial role in the regulation of many cellular processes and being linked to many diseases. Yet, there is still much to be understood regarding their functions and the biological pathways in which they are involved, as well as on the structural requirements that could drive the development of selective modulators of PRMT activity. Here we report a deconstruction–reconstruction approach that, starting from a series of type I PRMT inhibitors previously identified by us, allowed for the identification of potent and selective inhibitors of PRMT4, which regardless of the low cell permeability show an evident reduction of arginine methylation levels in MCF7 cells and a marked reduction of proliferation. We also report crystal structures with various PRMTs supporting the observed specificity and selectivity.

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Section: Resultsmentioning

confidence: 99%

Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction–Reconstruction and Fragment-Growing Approach

et al. 2022

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“…AML is one of the most common types of leukemia in adults and currently chemotherapy is still the mayor treatment for AML. However, the treatment effect is poor and there are still about 70 % of patients who obtain remission eventually relapse and evolve into refractory leukemia, leading to treatment failure and death [6][7][8] .…”

Section: Resultsmentioning

confidence: 99%

Tanshinone IIA Induces Apoptosis of Leukemia Cancer Cells and Inhibits Tumor Growth In Vivo Through Mitochondrial Pathway

Deng¹,

Tian²,

Chen³

2022

IJPS

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To investigate the effect of Tanshinone IIA on apoptosis of leukemic cancer cells and tumor growth inhibition in vivo. Human leukemia cell line HL-60 cells were divided into model group, low-dose group, medium dose group and high-dose group and transfected according to the groups. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide method was used to calculate the inhibition rate of cell growth, flow cytometry was used to detect the apoptosis rate and mitochondrial membrane potential and Western blot was used to detect mitochondrial membrane potential related protein. The treatment group was treated with Tanshinone IIA and the control group was given phosphate-buffered saline+dimethyl sulfoxide intraperitoneal injection. 2 w later, the tumor size and weight were measured and weighed. The 24 h and 48 h proliferation inhibition rates of the experimental group were significantly higher than those of the model group and increased with the increase of the dose (p<0.05). The early apoptosis rate and late apoptosis rate of the experimental group were significantly higher than those of the model group and increased with the increase of the dose (p<0.05). The level of integral optical density in the experimental group was significantly lower than that in the model group and decreased with the increase of the dose (p<0.05). The levels of caspase-9, caspase-3 and B-cell lymphoma 2 related X protein in the experimental group were significantly higher than those in the model group, while the level of B-cell lymphoma 2 in the experimental group was significantly lower than that in the model group and there was drug dependence (p<0.05). The tumor size and weight of the treatment group were significantly lower than those of the control group (p<0.05). Tanshinone IIA can induce apoptosis and tumor growth of leukemia cancer cells in vivo and slow down the proliferation of cancer cells, which may be related to the regulation of mitochondrial pathway and the inhibition of mitochondrial membrane potential related protein.

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“…Compounds targeting protein arginine methyltransferase 1 (PRMT1) [138] and PRMT5 [139] have reached the clinic (Table 5), and recently, the first proteolysis targeting chimera (PROTAC) PRMT5 degrader has been reported [140]. Selectivity toward PRMT4 was recently achieved [141].…”

Section: Successful Medicinal Chemistry Approaches and Clinical Trans...mentioning

confidence: 99%

Therapeutic targeting of chromatin: status and opportunities

Siklos

Kubicek

2021

The FEBS Journal

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The molecular characterization of mechanisms underlying transcriptional control and epigenetic inheritance since the 1990s has paved the way for the development of targeted therapies that modulate these pathways. In the past two decades, cancer genome sequencing approaches have uncovered a plethora of mutations in chromatin modifying enzymes across tumor types, and systematic genetic screens have identified many of these proteins as specific vulnerabilities in certain cancers. Now is the time when many of these basic and translational efforts start to bear fruit and more and more chromatin‐targeting drugs are entering the clinic. At the same time, novel pharmacological approaches harbor the potential to modulate chromatin in unprecedented fashion, thus generating entirely novel opportunities. Here, we review the current status of chromatin targets in oncology and describe a vision for the epigenome‐modulating drugs of the future.

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Design and Synthesis of Potent, Selective Inhibitors of Protein Arginine Methyltransferase 4 against Acute Myeloid Leukemia

Cited by 17 publications

References 47 publications

Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction–Reconstruction and Fragment-Growing Approach

Turning Nonselective Inhibitors of Type I Protein Arginine Methyltransferases into Potent and Selective Inhibitors of Protein Arginine Methyltransferase 4 through a Deconstruction–Reconstruction and Fragment-Growing Approach

Tanshinone IIA Induces Apoptosis of Leukemia Cancer Cells and Inhibits Tumor Growth In Vivo Through Mitochondrial Pathway

Therapeutic targeting of chromatin: status and opportunities

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