Abstract：
:To sustain their proliferation, cancer cells become dependent on one-carbon metabolism to support purine and thymidylate synthesis. Indeed, one of the most highly upregulated enzymes during neoplastic transformation is MTHFD2, a mitochondrial methylenetetrahydrofolate dehydrogenase and cyclohydrolase involved in one-carbon metabolism. Because MTHFD2 is expressed normally only during embryonic development, it offers a disease-selective therapeutic target for eradicating cancer cells while sparing healthy cells. Here we report the synthesis and preclinical characterization of the first inhibitor of human MTHFD2. We also disclose the first crystal structure of MTHFD2 in complex with a substrate-based inhibitor and the enzyme cofactors NAD+ and inorganic phosphate. Our work provides a rationale for continued development of a structural framework for the generation of potent and selective MTHFD2 inhibitors for cancer treatment. Cancer Res; 77(4); 937-48. ©2017 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Gustafsson R,Jemth AS,Gustafsson NM,Färnegårdh K,Loseva O,Wiita E,Bonagas N,Dahllund L,Llona-Minguez S,Häggblad M,Henriksson M,Andersson Y,Homan E,Helleday T,Stenmark Pdoi
10.1158/0008-5472.CAN-16-1476subject
Has Abstractpub_date
2017-02-15 00:00:00pages
937-948issue
4eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-16-1476journal_volume
77pub_type
杂志文章相关文献
CANCER RESEARCH文献大全abstract：:Vigorous activity after diagnosis was recently reported to be inversely associated with prostate cancer-specific mortality. However, men with metastatic disease may decrease their activity due to their disease; thus, a causal interpretation is uncertain. We therefore prospectively examined vigorous activity and brisk ...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-10-3932
更新日期：2011-06-01 00:00:00
abstract：:The histone demethylase KDM4B is frequently overexpressed in various cancer types, and previous studies have indicated that the primary oncogenic function of KDM4B is its ability to demethylate H3K9me3 in different tumors, resulting in altered gene expression and genome instability. A genome-wide analysis to evaluate ...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-18-1310
更新日期：2019-01-01 00:00:00
abstract：:The chemopreventive activity of two synthetic retinamides of relatively low toxicity against N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder cancer was studied in F344 rats and C57BL/6 X DBA/2 F1 mice. Female and male rats were given a total dose of either 1800 or 3200 mg OH-BBN over a period of...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1981-03-01 00:00:00
abstract：:Cell adhesion and spreading is a crucial step in the metastatic cascade of cancer cells, and interruption of this step is considered to be a logical strategy for prevention and treatment of tumor metastasis. Emodin is the major active component of the rhizome of Rheum palmatum L., with known anticancer activities. Her...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-06-0077
更新日期：2006-06-01 00:00:00
abstract：:Changes in binding of dexamethasone (9 alpha-fluoro-11 beta, 17 alpha, 21-trihydroxy-16 alpha-methylpregna-1,4-diene-3,20-dione) to its receptors in regenerating rat liver after 70% hepatectomy were examined. Specific receptors for dexamethasone in the liver remnants of adrenalectomized rats decreased significantly du...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1979-12-01 00:00:00
abstract：:CpG island methylation within promoters is known to silence individual genes in cancer. The involvement of this process in silencing gene pairs controlled by bidirectional promoters is unclear. In a screen for hypermethylated CpG islands in cancer, bidirectional promoters constituted 25.2% of all identified promoters,...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-05-2629
更新日期：2006-05-15 00:00:00
abstract：:Monoclonal antibodies (McAbs) to human bladder carcinoma were generated by fusion of NS-1 mouse myeloma cells with spleen cells from BALB/c mice immunized with either cultured human bladder cancer cells or cells obtained from a fresh surgically removed bladder tumor. Four hybridomas which reacted strongly with bladder...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1985-09-01 00:00:00
abstract：:4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (sum of which is denoted as total NNAL) are metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK and NNAL can induce lung cancer in laboratory animals but human data are limited. The association between prediagnostic levels o...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-08-4330
更新日期：2009-04-01 00:00:00
abstract：:The glutathione transferase (GST) isoenzyme profile was determined in two human tumor cell lines, U1690 derived from a small cell lung cancer and U1810 derived from a non-small cell lung cancer. U1810 cells are 3.2-fold more resistant to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) than are U1690 cells, a finding ascri...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1993-09-15 00:00:00
abstract：:Tumors of the central nervous system (CNS) often have sustained expression of labile genes, including angiogenic growth factors and immunosuppressive cytokines, which promote tumor progression. Stabilization of the RNA transcripts for these genes, such as vascular endothelial growth factor (VEGF), is an important mole...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-03-01 00:00:00
abstract：:The immune system is a robust and often untapped accomplice of many standard cancer therapies. A majority of tumors exist in a state of immune tolerance where the patient's immune system has become insensitive to the cancer cells. Because of its lymphodepleting effects, chemotherapy has the potential to break this tol...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-18-3712
更新日期：2019-10-15 00:00:00
abstract：:The gadd45 gene, a growth arrest and DNA damage (gadd)-induced gene, is transcriptionally activated by UV irradiation through two distinct pathways. One requires the sequence-specific binding of the p53 tumor suppressor protein to a responsive element within the third intron of the gadd45 gene, and the other is p53-in...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-02-01 00:00:00
abstract：:The presence of a quinone group in the structure of a series of model compounds was shown to produce cell kill by a mechanism involving free radicals and active oxygen species. Furthermore, the ability of the compound to bind to DNA appeared to enhance its cytocidal activity. The same model compounds were used to inve...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1984-01-01 00:00:00
abstract：:Rodent biliary glycoprotein (Bgp), also known as C-CAM, has recently been shown to function as a tumor suppressor in colon, prostate, and bladder cancers. This glycoprotein is a member of the carcinoembryonic antigen family and is one of the only proteins in this family to encode either a long (71-73 amino acids) or s...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1997-07-01 00:00:00
abstract：:Plasmids may have unique advantages as a gene delivery system. However, a major obstacle is the low in vivo transduction efficiency. In this study, an electroporation-based gene transduction approach was taken to study the effect of interleukin (IL)-2 or IL-12 gene transduction on the growth of experimental murine tum...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2001-04-15 00:00:00
abstract：:Aniline of unknown purity has been reported to induce spleen hemangiosarcoma in rats. Aniline has been found to be negative in terms of mutagenicity in both bacteria and yeasts. We have found that both commercial (already rather pure) and repurified aniline are clearly positive to a similar extent in inducing DNA dama...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1982-06-01 00:00:00
abstract：:IgG monoclonal antibodies have made significant contributions to cancer therapy, but suffer from several limitations that restrict their effectiveness in unleashing host immune system components against tumors. The development of monoclonal antibodies of an alternative class, namely IgE, may offer enhanced immune surv...
journal_title：Cancer research
pub_type： 杂志文章,评审
doi：10.1158/0008-5472.CAN-17-0428
更新日期：2017-06-01 00:00:00
abstract：:The autogenous humoral immune response of mice to their endogenous leukemia virus (MuLV) has been examined with respect to the reactivities of natural antibodies to MuLV envelope antigens and virus-induced cells surface antigens. The natural reactivity of MuLV envelope antigens was evaluated by means of a radioimmune ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1975-01-01 00:00:00
abstract：:We have isolated a Chinese hamster ovary cell line, designated ADR-1, which exhibits hypersensitivity to a range of drugs which are thought to inhibit the action of the enzyme topoisomerase II. These include anthracyclines, other classes of intercalating agents, and the epipodophyllotoxin, etoposide. No significant se...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1987-03-15 00:00:00
abstract：:Libraries of compounds are increasingly becoming commercially available for the use of individual academic laboratories. A high-throughput system based on a stably integrated transcriptional reporter was used to screen a library of random compounds to identify agents that conferred robust augmentation of a signal tran...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2000-06-15 00:00:00
abstract：:The cytotoxic, antimitotic, and growth inhibition properties of a photoactive analogue of vinblastine, N-(p-azidobenzoyl)-N'-beta-aminoethylvindesine (NABV), and vinblastine on P388 murine leukemia cells were compared. After 72-h exposure, the 50% drug-inhibitory concentrations for exponentially growing P388 leukemic ...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1987-10-01 00:00:00
abstract：:The toxicity and pharmacokinetics of cis-diamminedichloroplatinum (cisplatin) (90 mg/sq m) administered as a single 4-hr peritoneal dialysis, with or without concurrent i.v. infusion of sodium thiosulfate, 0.43 or 2.13 g/sq m/hr for 12 hr, were studied on 20 courses of treatment. When given without thiosulfate, the to...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1983-03-01 00:00:00
abstract：:Xeroderma pigmentosum (XP) and trichothiodystrophy (TTD) are rare genodermatoses transmitted as recessive and autosomal traits that result in reduced capacity to repair UV-induced DNA lesions. Although XP, but not TTD, patients are prone to basal and squamous cell carcinomas, to date no comparative studies of the XP a...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1999-03-15 00:00:00
abstract：:Cytogenetic analyses of intraspecies human HeLa X fibroblast hybrid cell populations have provided tentative evidence for the correlation of loss of a single copy of chromosomes 11 and 14 with reexpression of tumorigenicity. In this study paired combinations of nontumorigenic and tumorigenic segregant HeLa X fibroblas...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1986-12-01 00:00:00
abstract：:Recombinant immunotoxins (RIT) have been highly successful in cancer therapy due, in part, to the high cancer-specific expression of cell surface antigens such as mesothelin, which is overexpressed in mesothelioma, ovarian, lung, breast, and pancreatic cancers, but is limited in normal cells. RG7787 is a clinically op...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-15-2401
更新日期：2016-03-15 00:00:00
abstract：:Mouse myeloma cells were fused with spleen cells from BALB/c mice immunized with a cell line derived from human small cell carcinoma (SCC) of the lung. The cloned hybridoma SM1 produced antibody that was reactive with the surface membrane of SCC cell lines and SCC tumors but not with the membrane of several non-SCC ce...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1984-01-01 00:00:00
abstract：:Human squamous cell cancers are the most common epithelially derived malignancies. One example is esophageal squamous cell carcinoma (ESCC), which is associated with a high mortality rate that is related to a propensity for invasion and metastasis. Here, we report that periostin, a highly expressed cell adhesion molec...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-10-0704
更新日期：2010-07-01 00:00:00
abstract：:The basal layer of the epidermis and hair follicles is composed of actively cycling, transit-amplifying cells and quiescent cells including stem cells. To determine which population is the target of carcinogenic chemicals, we treated CD-1 female mice topically with 5-fluorouracil (5-FU), an agent known to kill cycling...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：1997-08-15 00:00:00
abstract：:Dickkopf3 (DKK3) is a secretory protein that belongs to the DKK family, but exhibits structural divergence from other family members, and its corresponding receptors remain to be identified. Although DKK3 has been shown to have oncogenic functions in certain cancer types, the underlying mechanism by which DKK3 promote...
journal_title：Cancer research
pub_type： 杂志文章
doi：10.1158/0008-5472.CAN-18-1749
更新日期：2018-11-01 00:00:00
abstract：:Insulin-like growth factors (IGFs) have mitogenic and antiapoptotic properties and have been implicated in the development of lung cancer. The effects of IGFs are modulated by insulin-like growth factor binding proteins (IGFBPs). This study explored the effects of IGFBP-3 on non-small cell lung cancer (NSCLC) cells af...
journal_title：Cancer research
pub_type： 杂志文章
doi：
更新日期：2002-06-15 00:00:00
