In vitro and in vivo induction of fetal hemoglobin with a reversible and selective DNMT1 inhibitor.

We report here the discovery of a novel class of orally bioavailable DNMT1-selective inhibitors as exemplified by GSK3482364. This molecule potently inhibits the methyltransferase activity of DNMT1, but not DNMT family members DNMT3A or DNMT3B. In contrast with cytidine analog DNMT inhibitors, the DNMT1 inhibitory mechanism of GSK3482364 does not require DNA incorporation and is reversible. In cultured human erythroid progenitor cells (EPCs), GSK3482364 decreased overall DNA methylation resulting in de-repression of the gamma globin genes HBG1 and HBG2 and increased HbF expression. In a transgenic mouse model of sickle cell disease, orally administered GSK3482364 caused significant increases in both HbF levels and in the percentage HbF-expressing erythrocytes, with good overall tolerability. We conclude that in these preclinical models, selective, reversible inhibition of DNMT1 is sufficient for the induction of HbF, and is well-tolerated. We anticipate that GSK3482364 will be a useful tool molecule for the further study of selective DNMT1 inhibition both in vitro and in vivo.
PMID: 32586904 [PubMed - as supplied by publisher]

Source: Haematologica - June 24, 2020 Category: Hematology Authors: Gilmartin AG, Groy A, Gore ER, Atkins C, Long ER, Montoute MN, Wu Z, Halsey W, McNulty DE, Ennulat D, Rueda L, Pappalardi M, Kruger RG, McCabe MT, Raoof A, Butlin R, Stowell A, Cockerill M, Waddell I, Ogilvie D, Luengo J, Jordan A, Benowitz AB Tags: Haematologica Source Type: research