Cycloguanil and Analogues Potently Target DHFR in Cancer Cells to Elicit Anti-Cancer Activity
department or school: Pharmaceutical Sciences, Faculty of
department or school: Non UBC
data provider: DSpace
identifier citation: Metabolites 13 (2): 151 (2023)
creator: Brown, Jennifer I.
creator: Wang, Peng
creator: Wong, Alan Y. L.
creator: Petrova, Boryana
creator: Persaud, Rosanne
creator: Soukhtehzari, Sepideh
creator: Lopez McDonald, Melanie
creator: Hanke, Danielle
creator: Christensen, Josephine
creator: Iliev, Petar
creator: Wang, Weiyuan
creator: Everton, Daniel K.
creator: Williams, Karla C.
creator: Frank, David A.
creator: Kanarek, Naama
creator: Page, Brent D. G.
issued: 2025-06-23T14:54:27Z
issued: 2023-01-19
description: Dihydrofolate reductase (DHFR) is an established anti-cancer drug target whose inhibition disrupts folate metabolism and STAT3-dependent gene expression. Cycloguanil was proposed as a DHFR inhibitor in the 1950s and is the active metabolite of clinically approved plasmodium DHFR inhibitor Proguanil. The Cycloguanil scaffold was explored to generate potential cancer therapies in the 1970s. Herein, current computational and chemical biology techniques were employed to re-investigate the anti-cancer activity of Cycloguanil and related compounds. In silico modeling was employed to identify promising Cycloguanil analogues from NCI databases, which were cross-referenced with NCI-60 Human Tumor Cell Line Screening data. Using target engagement assays, it was found that these compounds engage DHFR in cells at sub-nanomolar concentrations; however, growth impairments were not observed until higher concentrations. Folinic acid treatment rescues the viability impairments induced by some, but not all, Cycloguanil analogues, suggesting these compounds may have additional targets. Cycloguanil and its most promising analogue, NSC127159, induced similar metabolite profiles compared to established DHFR inhibitors Methotrexate and Pyrimethamine while also blocking downstream signaling, including STAT3 transcriptional activity. These data confirm that Cycloguanil and its analogues are potent inhibitors of human DHFR, and their anti-cancer activity may be worth further investigation.
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/91399
note: Citation: Brown, J.I.; Wang, P.; Wong,A.Y.L.; Petrova, B.; Persaud, R.;Soukhtehzari, S.; Lopez McDonald,M.; Hanke, D.; Christensen, J.; Iliev,P.; et al. Cycloguanil and AnaloguesPotently Target DHFR in CancerCells to Elicit Anti-Cancer Activity.Metabolites 2023, 13, 151. https://doi.org/10.3390/metabo13020151Academic Editor: Silvia RaveraReceived: 15 December 2022Revised: 14 January 2023Accepted: 16 January 2023Published: 19 January 2023Copyright: © 2023 by the authors.Licensee MDPI, Basel, Switzerland.This article is an open access articledistributed under the terms andconditions of the Creative CommonsAttribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).metabolitesHOHOHArticleCycloguanil and Analogues Potently Target DHFR in CancerCells to Elicit Anti-Cancer ActivityJennifer I. Brown 1, Peng Wang 2,3, Alan Y. L. Wong 2,4, Boryana Petrova 2,3 , Rosanne Persaud 1,Sepideh Soukhtehzari 1, Melanie Lopez McDonald 5, Danielle Hanke 1, Josephine Christensen 1, Petar Iliev 1,Weiyuan Wang 5 , Daniel K. Everton 1, Karla C. Williams 1, David A. Frank 5 , Naama Kanarek 2,3,6and Brent D. G. Page 1,*1 Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada2 Department of Pathology, Boston Children’s Hospital, Boston, MA 02115, USA3 Harvard Medical School, Boston, MA 02115, USA4 Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA5 Department of Hematology and Medical Oncology, Emory University, Atlanta, GA 30322, USA6 The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA* Correspondence: brent.page@ubc.caAbstract: Dihydrofolate reductase (DHFR) is an established anti-cancer drug target whose inhibitiondisrupts folate metabolism and STAT3-dependent gene expression. Cycloguanil was proposed as aDHFR inhibitor in the 1950s and is the active metabolite of clinically approved plasmodium DHFRinhibitor Proguanil. The Cycloguanil scaffold was explored to generate potential cancer therapiesin …
has type: Article
is shown at: 10.14288/1.0449164
language: eng
peer review status: Reviewed
provider: Vancouver : University of British Columbia Library
publisher: Multidisciplinary Digital Publishing Institute
publisher DOI: 10.3390/metabo13020151
rights: CC BY 4.0
rights URI: https://creativecommons.org/licenses/by/4.0/
scholar level: Faculty
scholar level: Researcher
subject: dihydrofolate reductase
subject: folate metabolism
subject: target engagement
subject: cancer therapy
subject: cycloguanil
subject: breast cancer
subject: STAT3
type: Text
identifier URI: http://hdl.handle.net/2429/91399