Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Department of Biomedical Sciences, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul, Republic of Korea; Chronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.
Eur J Med Chem. 2024 Dec 5;279:116843. doi: 10.1016/j.ejmech.2024.116843. Epub 2024 Sep 6.
Accumulating evidence reveals the oncogenic role of methyltransferase-like 3 (METTL3) in a variety of cancers, either dependent or independent of its mA 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 DC 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 mA-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.
越来越多的证据表明，甲基转移酶样 3（METTL3）在多种癌症中具有致癌作用，其依赖或不依赖 mA 甲基转移酶活性。我们已经探索了针对 METTL3 的 PROTACs，并鉴定出 KH12 是一种有效的 METTL3 降解剂。在 MOLM-13 细胞中用 KH12 处理会导致 METTL3 降解，在剂量、时间和泛素依赖性方式下，DC 值为 220 nM。此外，KH12 能够逆转分化，并具有抗增殖作用，超过了对 MOLM-13 细胞的小分子抑制剂。值得注意的是，我们首次提出 METTL3 降解剂可显著抑制多种胃癌（GC）细胞的生长，其中 METTL3 的非催化活性在肿瘤发生中起着关键作用。KH12 在患者来源的类器官（PDO）中的抗 GC 作用进一步得到证实。这项研究为针对与 METTL3 非催化功能相关的 GC 以及针对 AML 的 METTL3 靶向降解提供了治疗潜力。
