Rational Design of RNA Demethylase FTO Inhibitors with Enhanced Antileukemia Drug-Like Properties

Xiao, Pei; Duan, Zongliang; Liu, Zeyu; Chen, Liang; Zhang, Deyan; Liu, Lu; Zhou, Chunqin; Gan, Jianhua; Dong, Ze; Yang, Cai‐Guang

doi:10.1021/acs.jmedchem.3c00543

Cited by 16 publications

(8 citation statements)

References 70 publications

(163 reference statements)

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“…These results highlight the therapeutic significance for the development of small-molecule inhibitors that selectively targets certain m 6 A demethylase because FTO and ALKBH5 are homologous demethylases. 36 The development of selective FTO inhibitors by us and others has greatly progressed, 37 while the development of selective and highly potent inhibitors for ALKBH5 remains challenging.…”

Section: Discussionmentioning

confidence: 99%

A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO

Lai,

Li,

Zhu

et al. 2024

RSC Chem. Biol.

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Section: Discussionmentioning

confidence: 99%

A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO

Lai,

Li,

Zhu

et al. 2024

RSC Chem. Biol.

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“…The rigid chemical structure of compound 34 may affect its drug resistance, causing hindrance to subsequent drug development. To this end, Xiao [ 223 ] optimized tricyclic benzoic acid to tetracyclic benzoic acid and designed a new FTO inhibitor compound 35 (ZLD115, FTO IC 50 = 2.3 μM) (Fig. 11 A).…”

Section: Small-molecule Compounds Targeting M 6 a ...mentioning

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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“…For example, 2,4-pyridinedicarboxylic acid (2,4-PDCA) and 5-carboxy-8-hydroxyquinoline (IOX1) were identified to be FTO inhibitors as 2OG competitors. Rhein (the first FTO inhibitor), N-(5-Chloro-2,4-dihydroxyphenyl)-1-phenylcyclobutanecarboxamide (N-CDPCB), FTO-04, meclofenamic acid (MA), and a series of MA-derived inhibitors including FB23, FB23-2, Dac51, Dac85, and ZLD115 are substrate competitive inhibitors. Entacapone (an FDA-approved drug for Parkinson’s disease), hydrazide-based inhibitor (HZ), and an HZ-MA hybrid represent dual 2OG-substrate competitive FTO inhibitors.…”

Section: Chemical Intervention In M6a Modificationmentioning

confidence: 99%

Section: Chemical Intervention In M6a Modificationmentioning

confidence: 99%

“…Bringing drug-likeness into the picture, we incorporated flexible alkaline side chains at FB23’s solvent-accessible positions (Figure A) . Through a combination of SAR analysis and lipophilic efficiency (LipE)-guided optimization, we developed 44/ZLD115, a flexible alkaline side chain-substituted benzoic acid FTO inhibitor derived from FB23 with more balanced physicochemical properties and retained, or better antileukemia activity.…”

Section: Chemical Intervention In M6a Modificationmentioning

confidence: 99%

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Chemical Inhibitors Targeting the Oncogenic m⁶A Modifying Proteins

Huang,

Xia,

Dong

et al. 2023

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Epigenetics is brought to RNA, introducing a new dimension to gene expression regulation. Among numerous RNA modifications, N 6 -methyladenosine (m 6 A) is an abundant internal modification on eukaryote mRNA first identified in the 1970s. However, the significance of m 6 A modification in mRNA had been long neglected until the fat mass and obesity-associated (FTO) enzyme was identified as the first m 6 A demethylase almost 40 years later. The m 6 A modification influences nearly every step of RNA metabolism and thus broadly affects gene expression at multiple levels, playing a critical role in many biological processes, including cancer progression, metastasis, and immune evasion. The m 6 A level is dynamically regulated by RNA epigenetic machinery comprising methyltransferases such as methyltransferase-like protein 3 (METTL3), demethylases FTO and AlkB human homologue 5 (ALKBH5), and multiple reader proteins. The understanding of the biology of RNA epigenetics and its translational drug discovery is still in its infancy. It is essential to further develop chemical probes and lead compounds for an in-depth investigation into m 6 A biology and the translational discovery of anticancer drugs targeting m 6 A modifying oncogenic proteins.In this Account, we present our work on the development of chemical inhibitors to regulate m 6 A in mRNA by targeting the FTO demethylase, and the elucidation of their mode of action. We reported rhein to be the first substrate competitive FTO inhibitor. Due to rhein's poor selectivity, we identified meclofenamic acid (MA) that selectively inhibits FTO compared with ALKBH5. Based on the structural complex of MA bound with FTO, we designed MA analogs FB23-2 and Dac51, which exhibit significantly improved activities compared with MA. For example, FB23-2 is specific to FTO inhibition in vitro among over 400 other oncogenic proteins, including kinases, proteases, and DNA and histone epigenetic proteins. Mimicking FTO depletion, FB23-2 promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cells and inhibits the progression of primary cells in xenotransplanted mice. Dac51 treatment impairs the glycolytic activity of tumor cells and restores the function of CD8 + T cells, thereby inhibiting the growth of solid tumors in vivo. These FTO inhibitors were and will continue to be used as probes to promote biological studies of m 6 A modification and as lead compounds to target FTO in anticancer drug discovery.Toward the end, we also include a brief review of ALKBH5 demethylase inhibitors and METTL3 methyltransferase modulators.Collectively, these small-molecule modulators that selectively target RNA epigenetic proteins will promote in-depth studies on the regulation of gene expression and potentially accelerate anticancer target discovery.

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Rational Design of RNA Demethylase FTO Inhibitors with Enhanced Antileukemia Drug-Like Properties

Cited by 16 publications

References 70 publications

A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO

A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO

Small molecule inhibitors targeting m6A regulators

Chemical Inhibitors Targeting the Oncogenic m⁶A Modifying Proteins

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Rational Design of RNA Demethylase FTO Inhibitors with Enhanced Antileukemia Drug-Like Properties

Cited by 16 publications

References 70 publications

A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO

A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO

Small molecule inhibitors targeting m6A regulators

Chemical Inhibitors Targeting the Oncogenic m6A Modifying Proteins

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Product

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Chemical Inhibitors Targeting the Oncogenic m⁶A Modifying Proteins