Targeted degradation of METTL3 against acute myeloid leukemia and gastric cancer

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL European Journal of Medicinal Chemistry Pub Date : 2024-09-06 DOI:10.1016/j.ejmech.2024.116843

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Abstract

Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancers, either dependent or independent of its m⁶A methyl transferase activity. We have explored PROTACs targeting METTL3 and identified KH12 as a potent METTL3 degrader. Treatment of KH12 on MOLM-13 cells causes degradation of METTL3 with a DC₅₀ value of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition, KH12 is capable of reversing differentiation and possesses anti-proliferative effects surpassing the small molecule inhibitors on MOLM-13 cells. Notably, we first present that METTL3 degrader significantly suppresses the growth of various gastric cancer (GC) cells, where the m⁶A-independent activity of METTL3 plays a crucial role in tumorigenesis. The anti-GC effects of KH12 were further confirmed in patient-derived organoids (PDOs). This study offers therapeutic potentials of targeted degradation of METTL3 against GC implicated with non-catalytic function of METTL3 as well as against AML.

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越来越多的证据表明，类似甲基转移酶 3（METTL3）在多种癌症中具有依赖或独立于其 m6A 甲基转移酶活性的致癌作用。我们探索了针对 METTL3 的 PROTACs，发现 KH12 是一种有效的 METTL3 降解剂。对 MOLM-13 细胞进行 KH12 处理可导致 METTL3 降解，其 DC50 值为 220 nM，且具有剂量、时间和泛素依赖性。此外，KH12 还能逆转 MOLM-13 细胞的分化，并具有超越小分子抑制剂的抗增殖作用。值得注意的是，我们首次发现 METTL3 降解剂能显著抑制各种胃癌（GC）细胞的生长，而 METTL3 的 m6A 依赖性活性在肿瘤发生中起着至关重要的作用。KH12 的抗 GC 作用在患者衍生的器官组织（PDOs）中得到了进一步证实。这项研究提供了靶向降解 METTL3 的治疗潜力，可用于治疗与 METTL3 非催化功能有关的 GC 以及 AML。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.