Dataset Information

Rational Design and Optimization of m⁶A-RNA Demethylase FTO Inhibitors as Anticancer Agents.

ABSTRACT: Aberrant regulation of N⁶-methyladenosine (m⁶A) RNA modification has been implicated in the progression of multiple diseases, including cancer. Previously, we identified a small molecule inhibitor of the m⁶A demethylase fat mass- and obesity-associated protein (FTO), which removes both m⁶A and N⁶,2'-O-dimethyladenosine (m⁶A_m) RNA modifications. In this work, we describe the rational design and optimization of a new class of FTO inhibitors derived from our previous lead FTO-04 with nanomolar potency and high selectivity against the homologous m⁶A RNA demethylase ALKBH5. The oxetanyl class of compounds comprise competitive inhibitors of FTO with potent antiproliferative effects in glioblastoma, acute myeloid leukemia, and gastric cancer models where lead FTO-43 demonstrated potency comparable to clinical chemotherapeutic 5-fluorouracil. Furthermore, FTO-43 increased m⁶A and m⁶A_m levels in a manner comparable to FTO knockdown in gastric cancer cells and regulated Wnt/PI3K-Akt signaling pathways. The oxetanyl class contains significantly improved anticancer agents with a variety of applications beyond glioblastoma.

SUBMITTER: Huff S

PROVIDER: S-EPMC9421652 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Rational Design and Optimization of m6A-RNA Demethylase FTO Inhibitors as Anticancer Agents.

Huff Sarah S Kummetha Indrasena Reddy IR Zhang Lingzhi L Wang Lingling L Bray William W Yin Jiekai J Kelley Vanessa V Wang Yinsheng Y Rana Tariq M TM

Journal of medicinal chemistry 20220808 16

Aberrant regulation of N6-methyladenosine (m6A) RNA modification has been implicated in the progression of multiple diseases, including cancer. Previously, we identified a small molecule inhibitor of the m6A demethylase fat mass- and obesity-associated protein (FTO), which removes both m6A and N6,2'-O-dimethyladenosine (m6Am) RNA modifications. In this work, we describe the rational design and optim ...[more]

PMID: 35939803

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Project description:Uterine leiomyosarcoma (uLMS) is the most frequent subtype of uterine sarcoma that presents a poor prognosis and high rates of recurrence and metastasis. The origin and molecular mechanism underlying and driving its clinical and biological behavior remain largely unknown. Recently, we and others have revealed the role of microRNAs, DNA methylation, and histone modifications in contributing to the pathogenesis of uLMS. However, the connection between reversible m6A RNA methylation and uLMS pathogenesis remains unclear. In this study, we assessed the role and mechanism of FTO m6A RNA demethylase in the pathogenesis of uLMS. Immunohistochemistry analysis revealed that the levels of RNA demethylases FTO and ALKBH5 were aberrantly upregulated in uLMS tissues compared to adjacent myometrium with a significant change by histochemical scoring assessment (p < 0.01). Furthermore, the inhibition of FTO demethylase with its small, potent inhibitor (Dac51) significantly decreased the uLMS proliferation dose-dependently via cell cycle arrest. Notably, RNA-seq analysis revealed that the inhibition of FTO with Dac51 exhibited a significant decrease in cell-cycle-related genes, including several CDK members, and a significant increase in the expression of CDKN1A, which correlated with a Dac51-exerted inhibitory effect on cell proliferation. Moreover, Dac51 treatment allowed the rewiring of several critical pathways, including TNFα signaling, KRAS signaling, inflammation response, G2M checkpoint, and C-Myc signaling, among others, leading to the suppression of the uLMS phenotype. Moreover, transcription factor (TF) analyses suggested that epitranscriptional alterations by Dac51 may alter the cell cycle-related gene expression via TF-driven pathways and epigenetic networks in uLMS cells. This intersection of RNA methylation and other epigenetic controls and pathways provides a framework to better understand uterine diseases, particularly uLMS pathogenesis with a dysregulation of RNA methylation machinery. Therefore, targeting the vulnerable epitranscriptome may provide an additional regulatory layer for a promising and novel strategy for treating patients with this aggressive uterine cancer.

Dataset Information

Rational Design and Optimization of m⁶A-RNA Demethylase FTO Inhibitors as Anticancer Agents.

Publications

Rational Design and Optimization of m<sup>6</sup>A-RNA Demethylase FTO Inhibitors as Anticancer Agents.

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