6X9J

Human DNMT1(729-1600) Bound to Zebularine-Containing 12mer dsDNA and Inhibitor GSK3830052

Summary for 6X9J

• Entry DOI: 10.2210/pdb6x9j/pdb
• Descriptor: DNA (cytosine-5)-methyltransferase 1, DNA (5'-D(*GP*AP*GP*GP*CP*(5CM)P*GP*CP*CP*TP*GP*C)-3'), DNA (5'-D(*GP*CP*AP*GP*G)-R(P*(PYO))-D(P*GP*GP*CP*CP*TP*C)-3'), ... (7 entities in total)
• Functional Keywords: epigenetics, dna methyltransferase fold, maintenance methylation, inhibition, transferase, transferase-transferase inhibitor complex, transferase-transferase inhibitor-dna complex, transferase/transferase inhibitor/dna
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 107805.93

Authors

Pathuri, S.,Horton, J.R.,Cheng, X. (deposition date: 2020-06-02, release date: 2021-07-07, Last modification date: 2023-10-18)

Primary citation

Pappalardi, M.B.,Keenan, K.,Cockerill, M.,Kellner, W.A.,Stowell, A.,Sherk, C.,Wong, K.,Pathuri, S.,Briand, J.,Steidel, M.,Chapman, P.,Groy, A.,Wiseman, A.K.,McHugh, C.F.,Campobasso, N.,Graves, A.P.,Fairweather, E.,Werner, T.,Raoof, A.,Butlin, R.J.,Rueda, L.,Horton, J.R.,Fosbenner, D.T.,Zhang, C.,Handler, J.L.,Muliaditan, M.,Mebrahtu, M.,Jaworski, J.P.,McNulty, D.E.,Burt, C.,Eberl, H.C.,Taylor, A.N.,Ho, T.,Merrihew, S.,Foley, S.W.,Rutkowska, A.,Li, M.,Romeril, S.P.,Goldberg, K.,Zhang, X.,Kershaw, C.S.,Bantscheff, M.,Jurewicz, A.J.,Minthorn, E.,Grandi, P.,Patel, M.,Benowitz, A.B.,Mohammad, H.P.,Gilmartin, A.G.,Prinjha, R.K.,Ogilvie, D.,Carpenter, C.,Heerding, D.,Baylin, S.B.,Jones, P.A.,Cheng, X.,King, B.W.,Luengo, J.I.,Jordan, A.M.,Waddell, I.,Kruger, R.G.,McCabe, M.T.
Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia.
Nat Cancer, 2:1002-1017, 2021

PubMed 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.

PubMed: 34790902

Experimental method

X-RAY DIFFRACTION (1.79 Å)