A major disadvantage in fighting cancer is the low immunogenicity of cancer cells, impairing body’s ability to identify and destroy them. This paper describes STM3006, a novel, chemically distinct inhibitor of METTL3 with improved biochemical and cellular potency compared to the previously published ligand STM2457. Crystallography revealed improved binding within a newly formed ligand-induced lipophilic pocket within the protein, while retaining the interactions that provide high selectivity over other methyltransferases.
The authors demonstrated that METTL3 inhibition with STM3006 stimulates a cell-intrinsic interferon response through double-stranded RNA formation. This immunomodulatory mechanism is distinct from current immunotherapeutic agents and provides the molecular rationale for combination with anti-PD1 immune checkpoint blockade to augment anti-tumour immunity. In combination these therapies have demonstrated the ability to overcome malignant clones insensitive to the single agents.
This article is written in collaboration with Storm Therapeutics.