In vitro and in vivo induction of fetal hemoglobin with a reversible and selective DNMT1 inhibitor
Aidan G. Gilmartin,Arthur Groy,Elizabeth R. Gore,Charity Atkins,Edward Long,Monica N. Montoute,Zining Wu,Wendy S. Halsey,Dean E. McNulty,Daniela Ennulat,Lourdes Rueda,Melissa B. Pappalardi,Ryan G. Kruger,Michael T. McCabe,Ali Raoof,Roger J. Butlin,Alexandra Stowell,Mark Cockerill,Ian D. Waddell,Donald J. Ogilvie,Juan I. Luengo,Allan M. Jordan,Andrew B. Benowitz +22 more
TLDR
It is concluded that in these preclinical models, selective, reversible inhibition of DNMT1 is sufficient for the induction of HbF, and is well-tolerated.Abstract:Â
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 vivoread more
Citations
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References
More filters
Journal ArticleDOI
Sickle cell disease
TL;DR: New strategies for specific therapy, including expanded use of chronic transfusions, bone marrow transplantation, and hydroxyurea, now offer hope for prevention of many or all of the hemolytic and vaso-occlusive manifestations of sickle cell disease.
Journal ArticleDOI
Effect of Hydroxyurea on Mortality and Morbidity in Adult Sickle Cell Anemia: Risks and Benefits Up to 9 Years of Treatment
Martin H. Steinberg,Martin H. Steinberg,Franca B. Barton,Oswaldo Castro,Charles H. Pegelow,Samir K. Ballas,Abdullah Kutlar,Eugene P. Orringer,Rita Bellevue,Nancy F. Olivieri,James R. Eckman,Mala Varma,G. Ramirez,Brian Adler,Wally R. Smith,Timothy M. Carlos,Kenneth I. Ataga,Laura DeCastro,Carolyn Bigelow,Yogen Saunthararajah,Margaret Telfer,Elliott Vichinsky,Susan Claster,Susan Shurin,Kenneth Bridges,Myron A. Waclawiw,Duane Bonds,Michael L. Terrin +27 more
TL;DR: In a long-term observational follow-up study of mortality in patients with SCA who originally participated in the randomized, double-blind, placebo-controlled Multicenter Study of Hydroxyurea in Patients with Sickle Cell Anemia (MSH), conducted in 1992-1995, to determine whether hydroxyuraxurea attenuates mortality in Patients With SCA as discussed by the authors.
Journal ArticleDOI
The DNA methyltransferase family: a versatile toolkit for epigenetic regulation
TL;DR: Analysis of molecular interactions and changes in gene copy numbers modulate the activity of DNMTs in diverse gene regulatory functions, including transcriptional silencing, transcriptional activation and post-transcriptional regulation by DNMT2-dependent tRNA methylation enables the DNMT family to function as a versatile toolkit for epigenetic regulation.
Journal ArticleDOI
Covalent bond formation between a DNA-cytosine methyltransferase and DNA containing 5-azacytosine
TL;DR: It is demonstrated that azaC-DNA forms a covalent complex with Hpa II methylase, a bacterial enzyme that methylates the internal C of C-C-G-G sequences, which suggests that the inhibition is, at least in part, an active-site directed process and permits a proposal for the structure of the covalents complex.
Journal ArticleDOI
5-Aza-Deoxycytidine Induces Selective Degradation of DNA Methyltransferase 1 by a Proteasomal Pathway That Requires the KEN Box, Bromo-Adjacent Homology Domain, and Nuclear Localization Signal
Kalpana Ghoshal,Jharna Datta,Sarmila Majumder,Shoumei Bai,Huban Kutay,Tasneem Motiwala,Samson T. Jacob +6 more
TL;DR: Results demonstrate a unique mechanism for the selective degradation of DNMT1, the maintenance DNA methyltransferase, by well-known DNA-hypomethylating agents and indicate that covalent bond formation between the enzyme and 5-aza-CdR-incorporated DNA is not essential for enzyme degradation.
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