{"title":"靶向降解 METTL3，防治急性髓性白血病和胃癌","authors":"Kyubin Hwang , Juhyeon Bae , Yoo-Lim Jhe , Jungmin Kim , Jae-Ho Cheong , Ha-Soon Choi , Taebo Sim","doi":"10.1016/j.ejmech.2024.116843","DOIUrl":null,"url":null,"abstract":"<div><p>Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancers, either dependent or independent of its m<sup>6</sup>A methyl transferase activity. We have explored PROTACs targeting METTL3 and identified <strong>KH12</strong> as a potent METTL3 degrader. Treatment of <strong>KH12</strong> on MOLM-13 cells causes degradation of METTL3 with a DC<sub>50</sub> value of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition, <strong>KH12</strong> 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 m<sup>6</sup>A-independent activity of METTL3 plays a crucial role in tumorigenesis. The anti-GC effects of <strong>KH12</strong> 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.</p></div>","PeriodicalId":314,"journal":{"name":"European Journal of Medicinal Chemistry","volume":"279 ","pages":"Article 116843"},"PeriodicalIF":5.9000,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeted degradation of METTL3 against acute myeloid leukemia and gastric cancer\",\"authors\":\"Kyubin Hwang , Juhyeon Bae , Yoo-Lim Jhe , Jungmin Kim , Jae-Ho Cheong , Ha-Soon Choi , Taebo Sim\",\"doi\":\"10.1016/j.ejmech.2024.116843\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancers, either dependent or independent of its m<sup>6</sup>A methyl transferase activity. We have explored PROTACs targeting METTL3 and identified <strong>KH12</strong> as a potent METTL3 degrader. Treatment of <strong>KH12</strong> on MOLM-13 cells causes degradation of METTL3 with a DC<sub>50</sub> value of 220 nM in a dose-, time- and ubiquitin-dependent fashion. In addition, <strong>KH12</strong> 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 m<sup>6</sup>A-independent activity of METTL3 plays a crucial role in tumorigenesis. The anti-GC effects of <strong>KH12</strong> 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.</p></div>\",\"PeriodicalId\":314,\"journal\":{\"name\":\"European Journal of Medicinal Chemistry\",\"volume\":\"279 \",\"pages\":\"Article 116843\"},\"PeriodicalIF\":5.9000,\"publicationDate\":\"2024-12-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European Journal of Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0223523424007244\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/6 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European Journal of Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0223523424007244","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/6 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Targeted degradation of METTL3 against acute myeloid leukemia and gastric cancer
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.
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.
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