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. 2021 Oct;2(10):1002-1017.
Epub 2021 Sep 27.

Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia

Melissa B Pappalardi  1 , Kathryn Keenan  1 , Mark Cockerill  2   3 , Wendy A Kellner  1   3 , Alexandra Stowell  2 , Christian Sherk  1 , Kristen Wong  1 , Sarath Pathuri  4 , Jacques Briand  5 , Michael Steidel  6 , Philip Chapman  2 , Arthur Groy  7 , Ashley K Wiseman  8 , Charles F McHugh  1 , Nino Campobasso  5 , Alan P Graves  5 , Emma Fairweather  2 , Thilo Werner  6 , Ali Raoof  2 , Roger J Butlin  2 , Lourdes Rueda  1 , John R Horton  4 , David T Fosbenner  1 , Cunyu Zhang  1 , Jessica L Handler  1 , Morris Muliaditan  9 , Makda Mebrahtu  5 , Jon-Paul Jaworski  5 , Dean E McNulty  5 , Charlotte Burt  2 , H Christian Eberl  6 , Amy N Taylor  5 , Thau Ho  5 , Susan Merrihew  1 , Shawn W Foley  1 , Anna Rutkowska  6 , Mei Li  1 , Stuart P Romeril  1 , Kristin Goldberg  2 , Xing Zhang  4 , Christopher S Kershaw  2 , Marcus Bantscheff  6 , Anthony J Jurewicz  5 , Elisabeth Minthorn  1 , Paola Grandi  6 , Mehul Patel  5 , Andrew B Benowitz  7 , Helai P Mohammad  1 , Aidan G Gilmartin  7 , Rab K Prinjha  1 , Donald Ogilvie  2 , Christopher Carpenter  1 , Dirk Heerding  1 , Stephen B Baylin  10 , Peter A Jones  8 , Xiaodong Cheng  4 , Bryan W King  1 , Juan I Luengo  1 , Allan M Jordan  2 , Ian Waddell  2 , Ryan G Kruger  1 , Michael T McCabe  1
Affiliations

Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia

Melissa B Pappalardi et al. Nat Cancer. 2021 Oct.

Abstract

DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions. These agents induce notable toxicity to normal blood cells thus limiting their clinical doses. Herein we report the discovery of GSK3685032, a potent first-in-class DNMT1-selective inhibitor that was shown via crystallographic studies to compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA between two CpG base pairs. GSK3685032 induces robust loss of DNA methylation, transcriptional activation and cancer cell growth inhibition in vitro. Due to improved in vivo tolerability compared with decitabine, GSK3685032 yields superior tumor regression and survival mouse models of acute myeloid leukemia.

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Conflict of interest statement

Competing interests M.B.P., K.K., W.A.K., C.S., K.W., J.B., M.S., A.G., C.F.M., N.C., A.P.G., T.W., L.R., D.T.F., C.Z., J.L.H., M.Muliaditan, M.Mebrahtu, J.P.J., D.E.M., H.C.E., A.N.T., T.H., S.M., S.W.F., A. Rutkowska, M.L., S.P.R., M.B., A.J.J., E.M., P.G., M.P., A.B.B., H.P.M., A.G.G., R.K.P., C.C., D.H., B.W.K., J.I.L., R.G.K. and M.T.M. are/were employees and/or shareholders of GlaxoSmithKline (GSK). The remaining authors declare no competing interests.

Figures

Extended Data Fig. 1 |
Extended Data Fig. 1 |. Characterization of GSK3484862 and GSK3685032.
a, Stability of GSK3484862 (1,000 nM) as determined by LC-MS/MS in media without or with cells (MV4–11) at 37 °C versus decitabine (1,000 nM). b, Thermal profile (Tm, 77.5 °C, n = 2 biologically independent experiments with two technical replicates each) of the hemi-methylated hairpin oligonucleotide with DMSO or GSK3484862 (100 μM). c, DNMT1 activity (average of technical replicates, data is representative of two biologically independent experiments) for uninhibited reaction (DMSO, n = 2) and recovery of inhibited enzyme activity following rapid dilution (100-fold) of pre-complexed DNMT1:GSK3484862 (n = 3) or DNMT1:SAH (n = 3). d, Dose-dependent increase in vimentin expression (n = 2 biologically independent experiments with two technical replicates each) following treatment of DNMT3B ���/− HCT-116 cells with GSK3484862 or decitabine. e, Table summarizing up-regulation of vimentin expression in wild-type or DNMT3B −/− HCT-116 cells after treatment with GSK3484862 or decitabine (average ± s.d.; n = independently fitted EC50 values). f, IC50 values (bar represents average, n = biologically independent determinations) following a 0-minute (n = 15), 60-minute DNMT1:Inhibitor (EI, n = 2), or 60-minute DNMT1:Inhibitor:hemi-methylated DNA (ESI, n = 2) preincubation. g, Intact protein mass spectrometry for mDNMT1 (731–1602) following incubation with hemi-methylated DNA in the absence or presence of GSK3685032 showed no covalent adduct. h, Inhibition of a kinase panel (n = 369) by 10 μM GSK3685032. i, Inhibition of a methyltransferase panel by 10 μM GSK3685032. j, Isothermal dose-response curves for DNMT1 following treatment with GSK3685032 in a recombinant system (DNMT1 601–1600 in the presence of 40-mer hemi-methylated DNA) or in a cellular system (HepG2). k, Dose response curves (average ± s.d., n = biologically independent samples) for full-length DNMT1 using a 40-mer hemi-methylated or poly(dIdC) DNA substrate in a radioactive SPA assay with GSK3685032 (n = 4 or 5, respectively) or SAH (n = 4 or 6), respectively).
Extended Data Fig. 2 |
Extended Data Fig. 2 |. DNMT1 residues important for compound binding and inhibition.
a, Analogues containing a photoreactive benzophenone or diazerine moiety. b, c, Murine DNMT1 (731–1602) spectra in the absence or presence of a 45-minute photolysis step with 14-mer hemi-methylated DNA and GSK3844831 (b) or GSK3901839 (c). d, Dose response curves for HEK293 cells expressing either wild-type or site-directed alanine mutant DNMT1 (n = 2; technical replicates) treated for 6 days with decitabine or GSK3685032. Dashed line represents starting cell number (T0). e, Dose response curves (n = 4 biologically independent samples; average ± s.d.) for full-length wild-type or H1507Y DNMT1 activity in a radioactive SPA assay.
Extended Data Fig. 3 |
Extended Data Fig. 3 |. Sequence alignment of the methyltransferase domains of human DNMT1, DNMT3A, and DNMT3B.
Identical residues are shaded blue while similar residues are shaded yellow. The boxes indicate the target recognition domain of DNMT1 (dashed, black) and the active-site loop (solid, red). Residues that were photoaffinity labeled*, residues that conferred resistance to GSK3685032 upon mutation to alanine (gIC50 > 10 μM)† and are reported to be involved in recognition of the methylated cytosine‡, or the catalytic cysteine (C1226)♯ are marked within the DNMT1 sequence.
Extended Data Fig. 4 |
Extended Data Fig. 4 |. Crystal structure of DNMT1-DNA in complex with DNMT1 inhibitor.
a, View of the active-site loop bound in the space left by the flipped-out zebularine in the DNMT1-DNA complex. b, The omit electron density map in mesh for GSK3685032 contoured at 4σ above the mean. c, d, Orthogonal views of DNMT1-DNA in the presence of GSK3685032. The active-site loop is colored brown and adopts an open conformation. e, The omit electron density map in mesh for GSK3830052 contoured at 4σ above the mean. f, Superimposition of inhibitor (pink) and the active-site loop in the native complex (cyan). g, The inhibitor intercalates into DNA between two G:C base pairs. h, Two hydrogen bonds formed between G1 and zebularine. i, Inhibitor interacts with 5-methylcytosine (5mC) of the parent DNA strand and Trp1510 of DNMT1. j, The end of the inhibitor N-methyl-N-phenylmethanesulfonamide moiety is close to the DNMT1 active-site Cys1226.
Extended Data Fig. 5 |
Extended Data Fig. 5 |. Biochemical, phenotypic, and mechanistic activity of DNMT inhibitors.
a, Table reporting GSK3685032 activity in a panel of AML cell lines (day 6, average ± s.d., n = biologically independent experiments). b, Heatmap showing induction of caspase-glo 3/7 activity (Promega, average log2 fold change, n = 2 biologically independent experiments) in MV4–11 cells following treatment with GSK3510477, GSK3484862 (with 2 technical replicates), or GSK3685032 at days 1, 2, 4 & 6 (0.06–7,340 nM). c, Compound structures for reported DNMT inhibitors. d, Table containing output parameters (average ± SEM, n = biologically independent experiments) following biochemical, phenotypic (MV4–11, day 6) or mechanistic (MV4–11, day 4) assessment using a panel of DNMT inhibitors. NA, not applicable to assay format. 5mC, 5-methylcytosine. e, Top, Venn diagram for significantly increased genes in MV4–11 (RNA-seq, FDR < 0.05, |log2 fold-change| > 1, day 4, 400 nM) following treatment with GSK3685032 or decitabine. Bottom, Heatmap of log2 fold change differential expression (RNA-seq, day 4) following treatment with GSK3685032 or decitabine (3.2–10,000 nM) for overlapping genes (n = 1,542) from the Venn diagram.
Extended Data Fig. 6 |
Extended Data Fig. 6 |. Pharmacokinetic evaluation of GSK3685032.
a, Summary of mouse pharmacokinetic parameters for GSK3685032. NA, not applicable to dosing route. ND, value not determined. IV, intravenous. SC, subcutaneous. b, Blood concentration of GSK3685032 at multiple timepoints following a single dose of 2 mg/kg IV (male CD-1 mice), 2 mg/kg SC (male C57/BL6 mice), or 30 mg/kg SC (female Nu/Nu mice). Individual data shown (n = 3 animals/group). c, Dose proportional blood concentration of GSK3685032 following twice daily subcutaneous dosing for 8.5 days in a SKM-1 subcutaneous xenograft model (NOD-scid) collected 6 hours post last dose. Individual concentrations (n = 3 animals/group) with linear regression (R square = 0.9780) fit to the mean concentration for each group. d, Simulated profile of GSK3685032 over a 24 hour time frame adjusted for unbound fraction (2.5%) in the blood following twice daily subcutaneous dosing. 5-mC, 5-methylcytosine.
Extended Data Fig. 7 |
Extended Data Fig. 7 |. Compound effect in subcutaneous MV4–11 and SKM-1 xenograft models.
a, b, Animal body weight measurements for MV4–11 (a) or SKM-1 (b) xenograft models spanning the dosing duration of the study (average ± s.d.; n = 10 animals/group, # represents day first animal came off study due to tumor volume). c-f, Individual tumor volume measurements for MV4–11 (c, day 35) or SKM-1 (d, day 20). Solid line represents the median for each group (n = 10 animals unless noted). Dotted line represents the median tumor volume for vehicle. Statistical significance* of treatment versus vehicle was calculated using one-way ANOVA, Dunnett’s multiple comparisons test. Table summarizes adjusted P values to account for multiple comparisons and corresponding tumor growth inhibition (TGI) values for each group within the MV4–11 (e) or SKM-1 (f) xenograft models. g, h, Individual tumor volume measurements for the 45 mg/kg GSK3685032 group in MV4–11 (g) or SKM-1 (h) xenograft models during the dosing segment (orange bar) and continuing for ≥ 27 days off drug (blue bar) to monitor durability (n = 10 animals unless noted). The minimum measurable tumor volume was set to 10 mm3.
Extended Data Fig. 8 |
Extended Data Fig. 8 |. Effects of GSK3685032 and decitabine on complete blood cell counts.
a, b, Complete blood cell count (a) at day 28 across all dose groups (n = 5 animals/group; mean ± s.d.). Statistical significance* of treatment versus vehicle was calculated using one-way ANOVA, Dunnett’s multiple comparisons test. Each P value was adjusted to account for multiple comparisons. Table (b) showing output parameters following statistical analysis. Ûsed log10 transformed values due to unequal variance between groups. Ratio represents treatment group normalized to vehicle. c, Complete blood cell count (mean ± s.d.) at day 28 on treatment (n = 5 animals/group) followed by 27 days off treatment (n = 5 animals/group for 15 and 45 mg/kg or n = 8 animals for 30 mg/kg group) with GSK3685032.
Fig. 1 |
Fig. 1 |. Biochemical and cellular engagement of DNMT1 by GSK3484862.
a, GSK3484862 structure. b, GSK3484862 dose–response curves for the DNMT family generated using a fluorescence-coupled breaklight assay (n = 2 biologically independent experiments with two technical replicates each). c, Dose-dependent relationship between promoter methylation and gene expression of vimentin after treatment of DNMT3B −/− HCT-116 cells with GSK3484862 (n = 2 biologically independent experiments with two technical replicates each). d,e, Mouse embryonic fibroblast C3H/10T1/2 cells showing myotube formation after treatment with DAC (200 nM, 24 h, imaged at day 15) or GSK3484862 (2,000 nM, 72 h, imaged at day 28) (d) or adipocyte formation (imaged at day 28) after treatment with DAC (300 nM, 24 h) or GSK3484862 (200 nM, 72 h) (e). The phase-bright droplets have been previously shown to contain lipids. Dimethylsulfoxide (DMSO) control shows nondifferentiated, monolayered cells (imaged at day 28). Representative data from three independent experiments. f,g, Gene expression (n = 3 biologically independent samples; mean ± s.e.m.) of the muscle-specific differentiation factor Myod1 (f) or the adipocyte-specific differentiation factor Adipoq (g) in C3H/10T1/2 cells collected on the indicated days after treatment.
Fig. 2 |
Fig. 2 |. Biochemical and biophysical characterization of DNMT1-selective inhibitors.
a, GSK3685032 and GSK3830052 structures. b, GSK3685032 dose–response curves for the DNMT family generated using a radioactive SPA (n = 4 biologically independent samples; average ± s.d.). c, Thermal stabilization of recombinant DNMT1 (601–1600) upon compound treatment (0.13–50,000 nM) in the presence of 40-mer hemi-methylated DNA or unmethylated DNA, or in the absence of DNA. d, Structure of DNMT1–DNA where the DNA contains zebularine in place of the target cytidine (PDB 6X9I). e, DNMT1 in the absence of bound DNA (PDB 3SWR). f, Conformational changes of the active-site loop (residues 1224–1245). Left panel, DNMT1 with and without DNA. Right panel, DNMT1 in the absence of DNA or as part of the DNMT1–DNA–inhibitor complex. C, Cys1226; M, Met1232; P, Pro1225; S, Ser1237. g, Structure of DNMT1–DNA complex in the presence of GSK3830052 (PDB 6X9J). h, Close-up view of the inhibitor in the minor groove. i, Inhibitor-mediated interactions with residues in the DNA major groove side.
Fig. 3 |
Fig. 3 |. Phenotypic response following treatment with DNMT inhibitors in hematologic cancer cell lines.
a, GSK3685032 gIC50 and GDI values in a 6-d proliferation assay for 51 hematologic cell lines. b, Proliferation dose–response curves for MV4–11 cells treated with GSK3685032 spanning days 1–6 (n = 4 biologically independent experiments; average ± s.d.). Dotted lines represent cell growth of the vehicle control for each day. c, Potency (gIC50) and GDI values for MV4–11 cells treated with GSK3685032 or DAC over time (n = 4 biologically independent experiments; mean). d, Heatmap showing induction of caspase-glo 3/7 activity (Promega, log2; average of n = 2 biologically independent experiments) in a panel of AML cell lines following treatment with GSK3685032 (0.06–7,340 nM). e, Day 6 MV4–11 proliferation dose–response curves (n = 4 biologically independent experiments; average ± s.d.) for GSK3510477, GSK3484862 and GSK3685032. Dotted line represents starting cell number (T0) or vehicle growth (T6). f, MV4–11 proliferation dose–response curves at day 6 treated with a panel of DNMT inhibitors (GSK3685032 n = 7, MC3343 n = 6, SGI-1027 n = 2, RG-108 n = 3; n = biologically independent experiments; if n > 3, shown as average ± s.e.m.). Dotted line represents starting cell number (T0). g, Correlation plot of the day 6 GDI values (%) in 51 hematologic cell lines following treatment. MM, multiple myeloma.
Fig. 4 |
Fig. 4 |. GSK3685032 induces changes in DNA methylation and gene expression in treated cells.
a,b, DNA methylation profile (a, Infinium Methylation EPIC, line represents the mean, n = 866,091 probes) and the number of gene expression changes (b, RNA-seq) for GSK3685032 (400 nM)-treated cells over time. c,d, DNA methylation profile (c, Infinium Methylation EPIC, line represents the mean, n = 866,091 probes) and differential gene expression log2 fold-change heatmap (d, RNA-seq, n = 13,969 genes) for GSK3685032 (3.2–10,000 nM)-treated cells at day 4. e, Fold-change in promoter methylation and gene expression following treatment in MV4–11 cells (day 4) for genes (n = 4,424) with beta values in vehicle samples ≥0.8 ± 200 bp from transcription start site (TSS). f–h, DNA methylation profile (f, Infinium Methylation EPIC, n = 866,091 probes), heatmap of significant gene expression changes (g, RNA-seq, false discovery rate (FDR) < 0.05, |log2 fold change| > 1, n = 2,970 genes) and Venn diagram (h) showing the overlap of up- and down-regulated genes in MV4–11 cells treated with dimethylsulfoxide, GSK3510477 (10,000 nM), GSK3484862 (1,000 nM) or GSK3685032 (400 nM) for 4 d.
Fig. 5 |
Fig. 5 |. GSK3685032 activates immune response pathways.
a, Venn diagram of significantly changed genes FDR < 0.05, |log2 fold-change| >1) following treatment with GSK3685032 (400 nM, day 4, RNA-seq). b, Pathway analysis of significantly increased genes (FDR < 0.05, |log2 fold-change| > 1) following GSK3685032 treatment (400 nM, day 4, RNA-seq). c, GSEA plot for the Hallmark IFN-α gene set following GSK3685032 treatment (MV4–11, day 4, 400 nM, RNA-seq). NES, normalized enrichment score. d, log2 fold-change for representative genes involved in IFN response, viral sensing and antigen presentation in GSK3685032-treated cells (day 4, 400 nM, RNA-seq). Dotted line represents a twofold increase. e, Dose-dependent induction of CXCL11, IFI27, HLA-DQA1 and MAGEA4 (RT–qPCR, day 4, n = 3 biologically independent experiments) following treatment of MV4–11 cells with GSK3685032. f, Heatmap of Euclidian clustered log2 fold-change DEseq2 differential expression from cell lines treated with GSK3685032 or DAC (3.2–10,000 nM, day 4, RNA-seq) for the Hallmark IFN-α gene set (n = 93 genes).
Fig. 6 |
Fig. 6 |. Mechanistic evaluation of GSK3685032 and DAC in AML.
a, Changes in 5-methylcytosine (day 4, n = 2 biologically independent experiments) following treatment of MV4–11 cells. Dotted line represents the maximal average hypomethylation achieved by DAC or GSK3685032. b, Heatmap of log2 fold-change values for differentially expressed genes (n = 8,363 genes) in MV4–11 cells treated with GSK3685032 or DAC (3.2–10,000 nM, day 4, RNA-seq). c, Venn diagram showing the overlap of up- and down-regulated genes (day 4, MV4–11, RNA-seq). d, Up- and down-regulated gene expression changes (RNA-seq, FDR < 0.05, log2 fold change > 1 or < −1) in MV4–11 cells following treatment (400 nM) over time. e, Genome browser tracks of MV4–11 alignments separated by plus strand (scale, 0–50) and minus strand (scale, 0–2,600) for the human endogenous retroviral (ERV) element located within chr6:67,880,000–67,890,000 (subfamily H (HERVH), ERV1 family) demonstrating double-stranded transcripts. MV4–11 cells were treated with GSK3685032 (3.2–10,000 nM, day 4, RNA-seq). f, Dose-dependent (3.2–10,000 nM) differential hERV expression (n = 394 hERV families, log2 fold-change) in MV4–11 treated cells (day 4, RNA-seq). Box bounds show the 25th to 75th percentiles with the center at 50%, and whiskers show the 5th to 95th percentiles. g, Methylation beta values (Infinium Methylation EPIC, vehicle, day 4, MV4–11) for probes that fall at promoters with average beta value ≥0.8 (1,500 bp ± TSS, n = 13,185 probes), within an annotated hERV (n = 16,958 probes) or at promoters of combined Hallmark IFN-α and -γ genes from MsigDB (n = 205 probes). Box bounds show the 25th to 75th percentiles with the center at 50%, whiskers show the 5th to 95th percentiles and outliers are plotted as individual circles. h, Dose-dependent fold-change in hERV expression (RNA-seq, n = 394 hERV families) and methylation for all probes (n = 16,958 probes) on the Infinium Methylation EPIC array contained within an hERV (day 4, MV4–11). i, Time course of the average log2 fold-change in expression (RNA-seq) in MV4–11 cells treated with 400 nM GSK3685032 or DAC for genes with promotor beta values ≥0.8 (n = 12,352 genes), hERVs (n = 364 families) or IFN gene set (n = 219 genes).
Fig. 7 |
Fig. 7 |. Comparison of nucleoside versus non-nucleoside DNMT inhibitors.
a,b, Western blots were cropped to highlight protein(s) of interest. Images shown are from a single experiment, processed in parallel, and data are representative of two independent experiments. Uncropped images can be found in the source data. MW, molecular weight. a, Induction of ɣH2AX protein levels in MV4–11, GDM-1 or SKM-1 cells treated for 1, 2 or 4 d. Total H2AX is shown as a loading control. b, Changes in ɣH2AX, DNMT1, DNMT3A and DNMT3B protein levels in GDM-1 cells treated for 2 d with a titration of GSK3685032 or DAC (3.2–10,000 nM). Total H2AX and vinculin are shown as loading controls. c, Overlay showing proliferation (day 6, n = 4 biologically independent experiments; average ± s.d.), 5-methylcytosine (day 4, n = 2 biologically independent experiments) and significant gene expression (RNA-seq, FDR < 0.05, |log2 fold-change| > 1; day 4, average of n = 1,542 overlapping genes) changes in DAC- or GSK3685032-treated MV4–11 cells.
Fig. 8 |
Fig. 8 |. GSK3685032 reveals improved in vivo efficacy and tolerability in AML models compared with DAC.
a,b, Tumor volume measurements (n = 10 animals per group at each data point unless marked; average ± s.e.m.) for a subcutaneous MV4–11 (a) or SKM-1 (b) xenograft model following treatment with GSK3685032 (subcutaneous, twice daily) or DAC (intraperitoneal, three times weekly). c,d, Tumor volume measurements at study start, at last dose, and at the end of a dosing holiday for individual animals in a subcutaneous MV4–11 (c) or SKM-1 (d) xenograft model. Solid line represents the median for each group (n = 10 animals per group unless marked). Dotted line represents the median tumor volume for vehicle at study start. No animals remained in the vehicle group at study end (NA). One animal (30 mg kg−1, MV4–11 (c) and 45 mg kg−1, SKM-1 (d)) was inadvertently taken off study at the last dose and did not undergo observation for recovery. e, Kaplan–Meier plot showing animal survival in a disseminated MV4–11 model (n = 10 animals per group) where dosing occurred during the first 30 d. Statistical significance* was calculated using the log-rank (Mantel–Cox) test yielding P values for GSK3685032 of 0.1377 (1 mg kg−1), 0.8080 (5 mg kg−1), 0.0003 (15 mg kg−1), <0.0001 (30 mg kg−1) and <0.0001 (45 mg kg−1), or 0.0034 for DAC. f, Pharmacodynamic changes, measured as global 5-methylcytosine, in SKM-1 tumors (8.5 d, n = 3 animals per group, average ± s.d.). Dotted line represents vehicle control levels of 5-methylcytosine. g, Neutrophil, red blood cell and platelet counts from day 28 of the SKM-1 xenograft study. Solid line represents the median for each group (n = 5 animals). Statistical significance, listed as adjusted P value to account for multiple comparisons, of treatment versus vehicle was calculated using one-way ANOVA, Dunnett’s multiple comparisons test. Veh, vehicle.
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Comment in

  • The next generation of DNMT inhibitors.
    Mehdipour P, Chen R, De Carvalho DD. Mehdipour P, et al. Nat Cancer. 2021 Oct;2(10):1000-1001. doi: 10.1038/s43018-021-00271-z. Nat Cancer. 2021. PMID: 35121882 No abstract available.

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