Recent advances in the discovery of ALKBH 1-8 inhibitors

The AlkB family is a class of Fe(II) and α-ketoglutarate-dependent dioxygenases involved in the dealkylation of nucleobases of both DNA and RNA. The proteins belonging to this family share a common mechanism of action and participate in different pathways, from DNA repair to epigenetic regulation. Human cells have nine homologues, ALKBH1 - 8 and FTO.

This review gives focus to the discovery and development of ALKBH1 - 8 inhibitors. The authors discuss, from a medicinal chemistry point of view, the path that led to the discovery itself and the eventual structure-activity relationship emerged. The article is based on relevant literature published from 2021 to 2025 using PubMed.

The inhibition of ALKBH is of growing interest. These enzymes are involved in epigenetic regulation and in numerous pathologies, with compelling evidence of their involvement in many tumors, and we think that they represent a great therapeutic opportunity. Two critical difficulties must be faced in their developement: subtype selectivity and pharmacokinetic profile. Targeting the right subtype at a specific site of action is the most important goal for reaching their desired effect limiting epigenetic interference. To accomplish this, a better understanding of the molecular structures and mechanism of the ALKBH family is required.