In vitro and in vivo induction of fetal hemoglobin with a reversible and selective DNMT1 inhibitor
Long, ER, 3rd
Stowell, Alexandra I J
Cockerill, Mark J
Waddell, Ian D
Ogilvie, Donald J
Jordan, Allan M
AffiliationGlaxoSmithKline, Collegeville, Pennsylvania, USA;
MetadataShow full item record
AbstractPharmacological 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. Keywords: DNA methyltransferase; Fetal Hemoglobin; Hemoglobinopathies; Molecular Pharmacology; Sickle Cell Disease.
CitationGilmartin AG, Groy A, Gore ER, Atkins C, Long ER, 3rd, Montoute MN, et al. In vitro and in vivo induction of fetal hemoglobin with a reversible and selective DNMT1 inhibitor. Haematologica. 2020.
- Clinical studies with fetal hemoglobin-enhancing agents in sickle cell disease.
- Authors: Saunthararajah Y, DeSimone J
- Issue date: 2004 Oct
- Genome editing of HBG1 and HBG2 to induce fetal hemoglobin.
- Authors: Métais JY, Doerfler PA, Mayuranathan T, Bauer DE, Fowler SC, Hsieh MM, Katta V, Keriwala S, Lazzarotto CR, Luk K, Neel MD, Perry SS, Peters ST, Porter SN, Ryu BY, Sharma A, Shea D, Tisdale JF, Uchida N, Wolfe SA, Woodard KJ, Wu Y, Yao Y, Zeng J, Pruett-Miller S, Tsai SQ, Weiss MJ
- Issue date: 2019 Nov 12
- Oral tetrahydrouridine and decitabine for non-cytotoxic epigenetic gene regulation in sickle cell disease: A randomized phase 1 study.
- Authors: Molokie R, Lavelle D, Gowhari M, Pacini M, Krauz L, Hassan J, Ibanez V, Ruiz MA, Ng KP, Woost P, Radivoyevitch T, Pacelli D, Fada S, Rump M, Hsieh M, Tisdale JF, Jacobberger J, Phelps M, Engel JD, Saraf S, Hsu LL, Gordeuk V, DeSimone J, Saunthararajah Y
- Issue date: 2017 Sep
- Effects of 5-aza-2'-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease.
- Authors: Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, Gavazova S, Chen YH, Hoffman R, DeSimone J
- Issue date: 2003 Dec 1
- Neither DNA hypomethylation nor changes in the kinetics of erythroid differentiation explain 5-azacytidine's ability to induce human fetal hemoglobin.
- Authors: Mabaera R, Greene MR, Richardson CA, Conine SJ, Kozul CD, Lowrey CH
- Issue date: 2008 Jan 1