ArticleJournal of medicinal chemistry2016
Tumor Targeting with Novel 6-Substituted Pyrrolo [2,3-d] Pyrimidine Antifolates with Heteroatom Bridge Substitutions via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis.
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Article in Journal of medicinal chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 31 citations in OpenAlex.
- Mitochondrial and Cytosolic One-Carbon Metabolism Is a Targetable Metabolic Vulnerability in Cisplatin-Resistant Ovarian Cancer.Molecular cancer therapeutics · 2024Article
- Structural Characterization of 5-Substituted Pyrrolo[3,2-Biochemistry · 2024Article
- Discovery of Tumor-Targeted 6-Methyl Substituted Pemetrexed and Related Antifolates with Selective Loss of RFC Transport.ACS medicinal chemistry letters · 2023Article
- GART Functions as a Novel Methyltransferase in the RUVBL1/β-Catenin Signaling Pathway to Promote Tumor Stemness in Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Structure-Based Design of Transport-Specific Multitargeted One-Carbon Metabolism Inhibitors in Cytosol and Mitochondria.Journal of medicinal chemistry · 2023Article
- Multitargeted 6-Substituted Thieno[2,3-ACS pharmacology & translational science · 2023Article
- Biology and therapeutic applications of the proton-coupled folate transporter.Expert opinion on drug metabolism & toxicology · 2022Article
- Interaction mechanism of novel fluorescent antifolates targeted with folate receptors α and β via molecular docking and molecular dynamic simulations.Journal of molecular modeling · 2022Article
- Methionine synthase supports tumour tetrahydrofolate pools.Nature metabolism · 2021Article
- Discovery of 6-substituted thieno[2,3-d]pyrimidine analogs as dual inhibitors of glycinamide ribonucleotide formyltransferase and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase in de novo purine nucleotide biosynthesis in folate receptor expressing human tumors.Bioorganic & medicinal chemistry · 2021Article
- Design, synthesis and biological evaluation of novel pyrrolo[2,3-d]pyrimidine as tumor-targeting agents with selectivity for tumor uptake by high affinity folate receptors over the reduced folate carrier.Bioorganic & medicinal chemistry · 2020Article
- Preparation of Biphenyl-Conjugated Bromotyrosine for Inhibition of PD-1/PD-L1 Immune Checkpoint Interactions.International journal of molecular sciences · 2020Article
- Discovery of amide-bridged pyrrolo[2,3-d]pyrimidines as tumor targeted classical antifolates with selective uptake by folate receptor α and inhibition of de novo purine nucleotide biosynthesis.Bioorganic & medicinal chemistry · 2019Article
- Novel Pyrrolo[3,2-Molecular cancer therapeutics · 2019Article
- Fluorine-Substituted Pyrrolo[2,3- d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis.Journal of medicinal chemistry · 2018Article
- Development and validation of chemical features-based proton-coupled folate transporter/activity and reduced folate carrier/activity models (pharmacophores).Journal of molecular graphics & modelling · 2018Article
- Tumor Targeting with Novel Pyridyl 6-Substituted Pyrrolo[2,3- d]Pyrimidine Antifolates via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of De Novo Purine Nucleotide Biosynthesis.Journal of medicinal chemistry · 2018Article
- The promise and challenges of exploiting the proton-coupled folate transporter for selective therapeutic targeting of cancer.Cancer chemotherapy and pharmacology · 2018Review
- Progress in tumor-associated macrophage (TAM)-targeted therapeutics.Advanced drug delivery reviews · 2017Review
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Authors and funding
20 authors at 6 institutions in 2 countries.
Lalit K GolaniDivision of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
Adrianne Wallace-PovirkMolecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
Siobhan M DeisDepartment of Chemistry, Indiana University , Bloomington, Indiana 47405, United States.
Jennifer WongDepartment of Chemistry, Indiana University , Bloomington, Indiana 47405, United States.
Jiyuan KeLaboratory of Structural Sciences and Laboratory of Structural Biology and Biochemistry, Van Andel Research Institute , 333 Bostwick Avenue NE, Grand Rapids, Michigan 49503, United States.
Xin GuLaboratory of Structural Sciences and Laboratory of Structural Biology and Biochemistry, Van Andel Research Institute , 333 Bostwick Avenue NE, Grand Rapids, Michigan 49503, United States.
Sudhir RaghavanDivision of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
Mike R WilsonDepartment of Oncology, Wayne State University School of Medicine , Detroit, Michigan 48201, United States.
Xinxin LiDivision of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
Lisa PolinMolecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
Parker W de WaalLaboratory of Structural Sciences and Laboratory of Structural Biology and Biochemistry, Van Andel Research Institute , 333 Bostwick Avenue NE, Grand Rapids, Michigan 49503, United States.
Kathryn WhiteMolecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
Juiwanna KushnerMolecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
Carrie O'ConnorMolecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
Zhanjun HouMolecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
H Eric XuLaboratory of Structural Sciences and Laboratory of Structural Biology and Biochemistry, Van Andel Research Institute , 333 Bostwick Avenue NE, Grand Rapids, Michigan 49503, United States.
Karsten MelcherLaboratory of Structural Sciences and Laboratory of Structural Biology and Biochemistry, Van Andel Research Institute , 333 Bostwick Avenue NE, Grand Rapids, Michigan 49503, United States.
Charles E DannDepartment of Chemistry, Indiana University , Bloomington, Indiana 47405, United States.
Larry H MatherlyMolecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute , 110 East Warren Avenue, Detroit, Michigan 48201, United States.
Aleem GangjeeDivision of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University , 600 Forbes Avenue, Pittsburgh, Pennsylvania 15282, United States.
The Barbara Ann Karmanos Cancer Institute · USDuquesne University · USVan Andel Institute · USIndiana University Bloomington · USWayne State University · USChinese Academy of Sciences · CN
Funding
Tumor Biology and Microenvironment (Program 1)P30CA022453 · NCI · WAYNE STATE UNIVERSITY · PI PAUL M STEMMER · 1985 to 2026
$68.4MOverall EvaluationP41GM103403 · NIGMS · CORNELL UNIVERSITY · PI EALICK, STEVEN E · 2012 to 2017
$14.3MTRAINING IN GENETICST32GM007757 · NIGMS · TRUSTEES OF INDIANA UNIVERSITY · PI KUMAR, JUSTIN P · 1985 to 2014
$8.1MMOLECULAR REGULATION OF FOLATE AND ANTIFOLATE TRANSPORTR01CA053535 · NCI · WAYNE STATE UNIVERSITY · PI HOU, ZHANJUN, MATHERLY, LARRY H · 1993 to 2024
$6.3MTRAINING PROGRAM IN THE BIOLOGY OF CANCERT32CA009531 · NCI · WAYNE STATE UNIVERSITY · PI Larry H Matherly · 1985 to 2026
$5.3MStructural Genomics of Orphan Nuclear ReceptorsR01DK071662 · NIDDK · VAN ANDEL RESEARCH INSTITUTE · PI XU, H ERIC · 2005 to 2017
$5.1MDiscovery of novel PCFT-targeted agentsR01CA152316 · NCI · WAYNE STATE UNIVERSITY · PI GANGJEE, ALEEM, MATHERLY, LARRY H · 2011 to 2015
$2.3MPurine Synthesis Inhibitors with Selective Folate Receptor Tumor TransportR01CA166711 · NCI · DUQUESNE UNIVERSITY · PI DANN, CHARLES E., GANGJEE, ALEEM · 2013 to 2015
$1.7MStructural interrogation of allosteric AMPK regulationR01GM104212 · NIGMS · VAN ANDEL RESEARCH INSTITUTE · PI MELCHER, KARSTEN · 2013 to 2016
$1.5MMolecular Analyses of Folate and Antifolate TransportR01GM094472 · NIGMS · TRUSTEES OF INDIANA UNIVERSITY · PI DANN, CHARLES E. · 2010 to 2014
$1.4MAlpha Folate Receptor Mediated GARFTase Inhibitors as Selective Antitumor AgentsR01CA125153 · NCI · DUQUESNE UNIVERSITY · PI GANGJEE, ALEEM · 2006 to 2010
$1.3MStructural and functional analysis of a dynamic ABA signaling complexR01GM102545 · NIGMS · VAN ANDEL RESEARCH INSTITUTE · PI MELCHER, KARSTEN · 2012 to 2014
$1.1MNCI NIH HHS P30 CA022453NCI NIH HHS R01 CA053535NCI NIH HHS R01 CA125153NCI NIH HHS R01 CA152316NCI NIH HHS R01 CA166711NCI NIH HHS T32 CA009531NIDDK NIH HHS R01 DK071662NIGMS NIH HHS P41 GM103403NIGMS NIH HHS R01 GM094472NIGMS NIH HHS R01 GM102545NIGMS NIH HHS R01 GM104212NIGMS NIH HHS T32 GM007757
Abstract
Targeted antifolates with heteroatom replacements of the carbon vicinal to the phenyl ring in 1 by N (4), O (8), or S (9), or with N-substituted formyl (5), acetyl (6), or trifluoroacetyl (7) moieties, were synthesized and tested for selective cellular uptake by folate receptor (FR) α and β or the proton-coupled folate transporter. Results show increased in vitro antiproliferative activity toward engineered Chinese hamster ovary cells expressing FRs by 4-9 over the CH2 analogue 1. Compounds 4-9 inhibited de novo purine biosynthesis and glycinamide ribonucleotide formyltransferase (GARFTase). X-ray crystal structures for 4 with FRα and GARFTase showed that the bound conformations of 4 required flexibility for attachment to both FRα and GARFTase. In mice bearing IGROV1 ovarian tumor xenografts, 4 was highly efficacious. Our results establish that heteroatom substitutions in the 3-atom bridge region of 6-substituted pyrrolo[2,3-d]pyrimidines related to 1 provide targeted antifolates that warrant further evaluation as anticancer agents.
Indexed as
AnimalsAntineoplastic AgentsCell Line, TumorCrystallography, X-RayDrug Screening Assays, AntitumorFemaleFolate Receptor 1Folic Acid AntagonistsHeterograftsHumansMice, SCIDMolecular Docking SimulationNeoplasm TransplantationPhosphoribosylglycinamide FormyltransferaseProton-Coupled Folate TransporterPurine NucleotidesAntineoplastic AgentsFolate Receptor 1Folic Acid AntagonistsPhosphoribosylglycinamide FormyltransferaseProton-Coupled Folate TransporterPurine NucleotidesPyrimidinesPyrroles
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