Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia.

ABSTRACT: N⁶-methyladenosine (m⁶A) is an abundant internal RNA modification^1,2 that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex^3,4. The m⁶A methyltransferase METTL3 has been linked to the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown^5-7. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3-METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective r

SUBMITTER: Yankova E 

PROVIDER: S-EPMC7613134 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature