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对MTHFD2进行药理学靶向作用可通过诱导胸苷耗竭和复制应激来抑制急性髓系白血病。

Pharmacological targeting of MTHFD2 suppresses acute myeloid leukemia by inducing thymidine depletion and replication stress.

作者信息

Bonagas Nadilly, Gustafsson Nina M S, Henriksson Martin, Marttila Petra, Gustafsson Robert, Wiita Elisée, Borhade Sanjay, Green Alanna C, Vallin Karl S A, Sarno Antonio, Svensson Richard, Göktürk Camilla, Pham Therese, Jemth Ann-Sofie, Loseva Olga, Cookson Victoria, Kiweler Nicole, Sandberg Lars, Rasti Azita, Unterlass Judith E, Haraldsson Martin, Andersson Yasmin, Scaletti Emma R, Bengtsson Christoffer, Paulin Cynthia B J, Sanjiv Kumar, Abdurakhmanov Eldar, Pudelko Linda, Kunz Ben, Desroses Matthieu, Iliev Petar, Färnegårdh Katarina, Krämer Andreas, Garg Neeraj, Michel Maurice, Häggblad Sara, Jarvius Malin, Kalderén Christina, Jensen Amanda Bögedahl, Almlöf Ingrid, Karsten Stella, Zhang Si Min, Häggblad Maria, Eriksson Anders, Liu Jianping, Glinghammar Björn, Nekhotiaeva Natalia, Klingegård Fredrik, Koolmeister Tobias, Martens Ulf, Llona-Minguez Sabin, Moulson Ruth, Nordström Helena, Parrow Vendela, Dahllund Leif, Sjöberg Birger, Vargas Irene L, Vo Duy Duc, Wannberg Johan, Knapp Stefan, Krokan Hans E, Arvidsson Per I, Scobie Martin, Meiser Johannes, Stenmark Pål, Berglund Ulrika Warpman, Homan Evert J, Helleday Thomas

机构信息

Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, Solna, Sweden.

Department of Biochemistry & Biophysics, Stockholm University, Stockholm, Sweden.

出版信息

Nat Cancer. 2022 Feb;3(2):156-172. doi: 10.1038/s43018-022-00331-y. Epub 2022 Feb 28.

DOI:10.1038/s43018-022-00331-y
PMID:35228749
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8885417/
Abstract

The folate metabolism enzyme MTHFD2 (methylenetetrahydrofolate dehydrogenase/cyclohydrolase) is consistently overexpressed in cancer but its roles are not fully characterized, and current candidate inhibitors have limited potency for clinical development. In the present study, we demonstrate a role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar MTHFD2 inhibitors; protein cocrystal structures demonstrated binding to the active site of MTHFD2 and target engagement. MTHFD2 inhibitors reduced replication fork speed and induced replication stress followed by S-phase arrest and apoptosis of acute myeloid leukemia cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared with nontumorigenic cells. Mechanistically, MTHFD2 inhibitors prevented thymidine production leading to misincorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.

摘要

叶酸代谢酶MTHFD2（亚甲基四氢叶酸脱氢酶/环水解酶）在癌症中持续过表达，但其作用尚未完全明确，目前的候选抑制剂临床开发潜力有限。在本研究中，我们证明了MTHFD2在癌细胞DNA复制和基因组稳定性中的作用，并进行了药物筛选以鉴定强效且选择性的纳摩尔级MTHFD2抑制剂；蛋白质共晶体结构显示其与MTHFD2的活性位点结合并实现靶点结合。MTHFD2抑制剂降低了复制叉速度并诱导复制应激，随后导致急性髓系白血病细胞在体外和体内出现S期阻滞和凋亡，与非致瘤细胞相比，其治疗窗跨越四个数量级。从机制上讲，MTHFD2抑制剂阻止了胸苷的产生，导致尿嘧啶错误掺入DNA并引发复制应激。总体而言，这些结果证明了MTHFD2依赖性癌症代谢与复制应激之间的功能联系，可利用这类新型抑制剂进行治疗。

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