2. Academic Validation
  3. Targeted degradation of METTL3 against acute myeloid leukemia and gastric cancer

Targeted degradation of METTL3 against acute myeloid leukemia and gastric cancer

  • Eur J Med Chem. 2024 Sep 6:279:116843. doi: 10.1016/j.ejmech.2024.116843.
Kyubin Hwang 1,  Juhyeon Bae 1,  Yoo-Lim Jhe 2,  Jungmin Kim 2,  Jae-Ho Cheong 3,  Ha-Soon Choi 4,  Taebo Sim 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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; Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Republic of Korea.
  • 4 Magicbullettherapeutics Inc., 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
  • 5 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 Clinical Drug Discovery & Development, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea; Clinical Candidate Discovery & Development Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. Electronic address: TBSIM@yuhs.ac.
PMID: 39288597 DOI: 10.1016/j.ejmech.2024.116843
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.

Keywords

Acute myeloid leukemia; Gastric cancer; METTL3; Methyltransferase; PROTAC; Targeted protein degradation.

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