Pappalardi Melissa B, Keenan Kathryn, Cockerill Mark, Kellner Wendy A, Stowell Alexandra, Sherk Christian, Wong Kristen, Pathuri Sarath, Briand Jacques, Steidel Michael, Chapman Philip, Groy Arthur, Wiseman Ashley K, McHugh Charles F, Campobasso Nino, Graves Alan P, Fairweather Emma, Werner Thilo, Raoof Ali, Butlin Roger J, Rueda Lourdes, Horton John R, Fosbenner David T, Zhang Cunyu, Handler Jessica L, Muliaditan Morris, Mebrahtu Makda, Jaworski Jon-Paul, McNulty Dean E, Burt Charlotte, Eberl H Christian, Taylor Amy N, Ho Thau, Merrihew Susan, Foley Shawn W, Rutkowska Anna, Li Mei, Romeril Stuart P, Goldberg Kristin, Zhang Xing, Kershaw Christopher S, Bantscheff Marcus, Jurewicz Anthony J, Minthorn Elisabeth, Grandi Paola, Patel Mehul, Benowitz Andrew B, Mohammad Helai P, Gilmartin Aidan G, Prinjha Rab K, Ogilvie Donald, Carpenter Christopher, Heerding Dirk, Baylin Stephen B, Jones Peter A, Cheng Xiaodong, King Bryan W, Luengo Juan I, Jordan Allan M, Waddell Ian, Kruger Ryan G, McCabe Michael T
Cancer Epigenetics Research Unit, Oncology, GlaxoSmithKline, Collegeville, PA, USA.
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Alderley Park, Macclesfield, UK.
Nat Cancer. 2021 Oct;2(10):1002-1017. Epub 2021 Sep 27.
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.
DNA甲基化是转录沉默的关键表观遗传驱动因素，在癌症中普遍失调。通过低甲基化剂（如胞苷类似物地西他滨或阿扎胞苷）逆转DNA甲基化已在血液系统恶性肿瘤中显示出临床益处。这些核苷类似物被掺入复制的DNA中，通过不可逆的共价相互作用抑制DNA胞嘧啶甲基转移酶DNMT1、DNMT3A和DNMT3B。这些药物对正常血细胞具有显著毒性，因此限制了它们的临床剂量。在此，我们报告了GSK3685032的发现，这是一种强效的、同类首创的DNMT1选择性抑制剂，通过晶体学研究表明，它与DNMT1的活性位点环竞争，以穿透两个CpG碱基对之间的半甲基化DNA。GSK3685032在体外可诱导强烈的DNA甲基化缺失、转录激活和癌细胞生长抑制。与地西他滨相比，由于体内耐受性提高，GSK3685032在急性髓系白血病的小鼠模型中产生了更好的肿瘤消退和生存效果。
