METTL3 Inhibitors for Epitranscriptomic Modulation of Cellular Processes

Abstract

The methylase METTL3 is the writer enzyme of the N 6 -methyladenosine (m 6 A) modification of RNA. Using a structure-based drug discovery approach, we identified a METTL3 inhibitor with potency in a biochemical assay of 280 nM, while its enantiomer is 100 times less active. We observed a dose-dependent reduction in the m 6 A methylation level of mRNA in several cell lines treated with the inhibitor already after 16 h of treatment, which lasted for at least 6 days. Importantly, the prolonged incubation (up to 6 days) with the METTL3 inhibitor did not alter levels of other RNA modifications (i. e., m 1 A, m 6 A m , m 7 G), suggesting selectivity of the developed compound towards other RNA methyltransferases.

m6A modification: recent advances, anticancer targeted drug discovery and beyond

“…4 ) was identified. It was further validated to selectively bind to METTL3 by X-ray crystallography, and it slightly suppresses the expression of METTL3 but significantly reduces m6A levels in the mRNA fraction in the leukemia cell line MOLM-13 and human osteosarcoma U2OS cells [ 216 ].…”

The Role of RNA Methyltransferase METTL3 in Normal and Malignant Hematopoiesis

“…STM2457 can prevent AML expansion and impair leukemia stem cells in both a patient-derived xenograft (PDX) model and a primary mouse MLL-AF9/Flt3 itd/+ model ( 78 ). Another METTL3 -selective inhibitor, UZH1a, a high-nanomolar inhibitor, occupies the SAM binding site of METTL3 , similar to STM2457 ( 79 ). UZH1a could also result in a decrease in the mRNA m 6 A methylation level in AML MOLM-13 cells in a dose-dependent manner (IC50 of 7 µM) ( 79 ).…”

“…Another METTL3 -selective inhibitor, UZH1a, a high-nanomolar inhibitor, occupies the SAM binding site of METTL3 , similar to STM2457 ( 79 ). UZH1a could also result in a decrease in the mRNA m 6 A methylation level in AML MOLM-13 cells in a dose-dependent manner (IC50 of 7 µM) ( 79 ). Furthermore, this group also confirmed that UZH1a could reduce mRNA m 6 A/A levels not only in the leukemia cell line MOLM-13 but also in other cell lines (osteosarcoma U2OS cells and immortalized human embryonic kidney cell line HEK293T).…”

Emerging role of m6A methylation modification in ovarian cancer

“…No cellular data were obtained in Bedi’s work. To date, there are two different selective small molecule inhibitors of METTL3, namely, STM2457 and UZH1a, which were independently reported by Yankova et al and Moroz-Omori et al [ 146 , 147 ]. When binding with METTL3, the two inhibitors both occupy the SAM-binding site and reorganize Lys 513 of METTL3, which partly contributes to their selectivity.…”

“…Consistently, SAM and sinefungin, pan inhibitors of methyltransferases, do not possess a specific binding mode [ 148 ]. Although the activity of STM2457 and UZH1a in OC is still unknown, both STM2457 and UZH1a could dampen the activity of METTL3 in the AML cell line MOLM-13 [ 146 , 147 ]. Moreover, the propagation of several AML cell lines from human or mouse was blocked by STM2457 [ 146 ].…”