Discovery of potent DNMT1 inhibitors against sickle cell disease using structural-based virtual screening, MM-GBSA and molecular dynamics simulation-based approaches

Article

作者: Sankaranarayanan, Murugesan ; Gupta, Pragya ; Ala, Chandu ; Ramalingam, Sivaprakash ; Joshi, Renuka Parshuram

Sickle cell disease (SCD) is an autosomal recessive genetic disorder affecting millions of people worldwide. A reversible and selective DNMT1 inhibitor, GSK3482364, has been known to decrease the overall methylation activity of DNMT1, resulting in the increase of HbF levels and percentage of HbF-expressing erythrocytes in an in vitro and in vivo model. In this study, a structure-based virtual screening was done with GSK3685032, a co-crystalized ligand of DNMT1 (PDB ID: 6X9K) with an IC₅₀ value of 0.036 μM and identified 3988 compounds from three databases (ChEMBL, PubChem and Drug Bank). Using this screening method, we identified around 15 compounds with XP docking scores greater than -8 kcal/mol. Further, prime MM-GBSA calculations have been performed and found compound SCHEMBL19716714 with the highest binding free energy of -83.31 kcal/mol. Finally, four compounds were identified based on glide energy and ΔG bind scores that have the most binding with DG7, DG19, DG20 bases and Lys1535, His1507, Trp1510, Ser1230, which were required for the target enzyme inhibition. Furthermore, molecular dynamics simulation studies of top ligands validate the stability of the docked complexes by examining root mean square deviations, root mean square fluctuations, solvent accessible surface area, and radius of gyration graphs from simulation trajectories. These findings suggest that the top four hit compounds may be capable of inhibiting DNMT1 and that additional in vitro and in vivo studies will be essential to prove the clinical effectiveness of the selected lead compounds.Communicated by Ramaswamy H. Sarma.

Nature Cancer

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

Article

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

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.

Communications Biology

Chromosome-specific retention of cancer-associated DNA hypermethylation following pharmacological inhibition of DNMT1

Article

作者: Tiedemann, Rochelle L ; Fan, Huihui ; Madaj, Zachary ; Shen, Hui ; Pappalardi, Melissa B ; Wiseman, Ashley K ; McCabe, Michael T ; Jones, Peter A

AbstractThe DNA methylation status of the X-chromosome in cancer cells is often overlooked because of computational difficulties. Most of the CpG islands on the X-chromosome are mono-allelically methylated in normal female cells and only present as a single copy in male cells. We treated two colorectal cancer cell lines from a male (HCT116) and a female (RKO) with increasing doses of a DNA methyltransferase 1 (DNMT1)-specific inhibitor (GSK3685032/GSK5032) over several months to remove as much non-essential CpG methylation as possible. Profiling of the remaining DNA methylome revealed an unexpected, enriched retention of DNA methylation on the X-chromosome. Strikingly, the identified retained X-chromosome DNA methylation patterns accurately predicted de novo DNA hypermethylation in colon cancer patient methylomes in the TCGA COAD/READ cohort. These results suggest that a re-examination of tumors for X-linked DNA methylation changes may enable greater understanding of the importance of epigenetic silencing of cancer related genes.

100 项与 GSK-3685032 相关的药物交易

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