The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression

Hong, Yun-Guang; Yang, Zhigang; Chen, Yan; Liu, Tian; Zheng, Yuyuan; Chun, Zhang; Wu, Gang; Chen, Yinhui; Xia, Juan; Wen, Ruiting; Liu, Wenxin; Zhao, Yi; Chen, Jin; Gao, Xiangwei; Chen, Zhanghui

doi:10.1158/0008-5472.can-21-4249

Cited by 34 publications

(11 citation statements)

References 42 publications

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“…The crude product was purified using flash column chromatography (SiO 2 ; EtOAc/Hept = 1:1) and the desired compound was obtained as a white solid (0.12 g, 81%). 1 2-Chloro-9-(3-chlorobenzyl)-N-methyl-9H-purin-6-amine (25). The final compound was prepared following the General method 2 starting from corresponding compound 38 (0.272 g, 0.867 mmol).…”

Section: -(3-(2h-tetrazol-5-yl)benzyl)-2-chloro-n-methyl-9h-purin-6am...mentioning

confidence: 99%

Structure-Based Design of a Potent and Selective YTHDC1 Ligand

Zálešák,

Nai,

Herok

et al. 2024

J. Med. Chem.

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N 6 -Adenosine methylation (m 6 A) is a prevalent post-transcriptional modification of mRNA, with YTHDC1 being the reader protein responsible for recognizing this modification in the cell nucleus. Here, we present a protein structure-based medicinal chemistry campaign that resulted in the YTHDC1 inhibitor 40, which shows an equilibrium dissociation constant (K d ) of 49 nM. The crystal structure of the complex (1.6 Å resolution) validated the design. Compound 40 is selective against the cytoplasmic m 6 A-RNA readers YTHDF1−3 and YTHDC2 and shows antiproliferative activity against the acute myeloid leukemia (AML) cell lines THP-1, MOLM-13, and NOMO-1. For the series of compounds that culminated into ligand 40, the good correlation between the affinity in the biochemical assay and antiproliferative activity in the THP-1 cell line provides evidence of YTHDC1 target engagement in the cell. The binding to YTHDC1 in the cell is further supported by the cellular thermal shift assay. Thus, ligand 40 is a tool compound for studying the role of YTHDC1 in AML.

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Section: -(3-(2h-tetrazol-5-yl)benzyl)-2-chloro-n-methyl-9h-purin-6am...mentioning

confidence: 99%

Structure-Based Design of a Potent and Selective YTHDC1 Ligand

Zálešák,

Nai,

Herok

et al. 2024

J. Med. Chem.

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“…Similarly, IGF2BP3 stabilizes the expression of regulator of chromosome condensation 2 (RCC2) mRNA to promote AML progression [ 112 ]. The YTH family is an important component of m 6 A readers, and both YTHDF1 [ 113 ] and YTHDF2 [ 114 ] promote AML cell proliferation by regulating m 6 A methylation. Yarmishyn [ 115 ] reported Musashi-1 (MSI1), a post-transcriptional gene expression regulator implicated in GBM, whose expression is positively correlated with YTHDF1.…”

Section: Potential Of M 6 a In Cancer Therapymentioning

confidence: 99%

Small molecule inhibitors targeting m6A regulators

Feng,

Wu,

et al. 2024

J Hematol Oncol

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As the most common form of epigenetic regulation by RNA, N6 methyladenosine (m6A) modification is closely involved in physiological processes, such as growth and development, stem cell renewal and differentiation, and DNA damage response. Meanwhile, its aberrant expression in cancer tissues promotes the development of malignant tumors, as well as plays important roles in proliferation, metastasis, drug resistance, immunity and prognosis. This close association between m6A and cancers has garnered substantial attention in recent years. An increasing number of small molecules have emerged as potential agents to target m6A regulators for cancer treatment. These molecules target the epigenetic level, enabling precise intervention in RNA modifications and efficiently disrupting the survival mechanisms of tumor cells, thus paving the way for novel approaches in cancer treatment. However, there is currently a lack of a comprehensive review on small molecules targeting m6A regulators for anti-tumor. Here, we have comprehensively summarized the classification and functions of m6A regulators, elucidating their interactions with the proliferation, metastasis, drug resistance, and immune responses in common cancers. Furthermore, we have provided a comprehensive overview on the development, mode of action, pharmacology and structure–activity relationships of small molecules targeting m6A regulators. Our aim is to offer insights for subsequent drug design and optimization, while also providing an outlook on future prospects for small molecule development targeting m6A.

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“…This remarkable medication has the ability to directly disrupt the binding between YTHDF1 and m6A-mRNA, thus inhibiting YTHDF1’s translation of cyclin E2 and subsequently slowing down cancer progression. Tegaserod, known as a 5-HT4 receptor agonist, is commonly utilized in the treatment of irritable bowel syndrome with constipation (IBS-C) [ 115 , 116 ]. It is foreseeable that with the continuous synthesis and development of various small molecules, coupled with the significant impact of YTHDF1 on tumors, YTHDF1 will increasingly emerge as a crucial target protein.…”

Section: Ythdf1 and Cancer Therapymentioning

confidence: 99%

YTHDF1 in Tumor Cell Metabolism: An Updated Review

Rong,

Wang,

Wang

et al. 2023

Molecules

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With the advancement of research on m6A-related mechanisms in recent years, the YTHDF protein family within m6A readers has garnered significant attention. Among them, YTHDF1 serves as a pivotal member, playing a crucial role in protein translation, tumor proliferation, metabolic reprogramming of various tumor cells, and immune evasion. In addition, YTHDF1 also exerts regulatory effects on tumors through multiple signaling pathways, and numerous studies have confirmed its ability to assist in the reprogramming of the tumor cell-related metabolic processes. The focus of research on YTHDF1 has shifted in recent years from its m6A-recognition and -modification function to the molecular mechanisms by which it regulates tumor progression, particularly by exploring the regulatory factors that interact with YTHDF1 upstream and downstream. In this review, we elucidate the latest signaling pathway mechanisms of YTHDF1 in various tumor cells, with a special emphasis on its distinctive characteristics in tumor cell metabolic reprogramming. Furthermore, we summarize the latest pathological and physiological processes involving YTHDF1 in tumor cells, and analyze potential therapeutic approaches that utilize YTHDF1. We believe that YTHDF1 represents a highly promising target for future tumor treatments and a novel tumor biomarker.

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The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression

Cited by 34 publications

References 42 publications

Structure-Based Design of a Potent and Selective YTHDC1 Ligand

Structure-Based Design of a Potent and Selective YTHDC1 Ligand

Small molecule inhibitors targeting m6A regulators

YTHDF1 in Tumor Cell Metabolism: An Updated Review

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