@article{Aidan G. Gilmartin_Arthur Groy_Elizabeth R. Gore_Charity Atkins_Edward R. Long_Monica N. Montoute_Zining Wu_Wendy Halsey_Dean E. McNulty_Daniela Ennulat_Lourdes Rueda_Melissa Pappalardi_Ryan G. Kruger_Michael T. McCabe_Ali Raoof_Roger Butlin_Alexandra Stowell_Mark Cockerill_Ian Waddell_Donald Ogilvie_Juan Luengo_Allan Jordan_Andrew B. Benowitz_2021, place={Pavia, Italy}, title={<i>In vitro</i> and <i>in vivo</i> induction of fetal hemoglobin with a reversible and selective DNMT1 inhibitor}, volume={106}, url={https://haematologica.org/article/view/9791}, DOI={10.3324/haematol.2020.248658}, abstractNote={<p>Pharmacological induction of fetal hemoglobin (HbF) expression is an effective therapeutic strategy for the management of beta-hemoglobinopathies such as sickle cell disease. DNA methyltransferase (DNMT) inhibitors 5-azacytidine (5-aza) and 5-aza-2′-deoxycytidine (decitabine) have been shown to induce fetal hemoglobin expression in both preclinical models and clinical studies, but are not currently approved for the management of hemoglobinopathies. 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.</p&gt;}, number={7}, journal={Haematologica}, author={Aidan G. Gilmartin and Arthur Groy and Elizabeth R. Gore and Charity Atkins and Edward R. Long and Monica N. Montoute and Zining Wu and Wendy Halsey and Dean E. McNulty and Daniela Ennulat and Lourdes Rueda and Melissa Pappalardi and Ryan G. Kruger and Michael T. McCabe and Ali Raoof and Roger Butlin and Alexandra Stowell and Mark Cockerill and Ian Waddell and Donald Ogilvie and Juan Luengo and Allan Jordan and Andrew B. Benowitz}, year={2021}, month={Jul.}, pages={1979-1987} }