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Mol Cancer Ther. 2019 Oct;18(10):1787-1799. doi: 10.1158/1535-7163.MCT-19-0037. Epub 2019 Jul 9.

Novel Pyrrolo[3,2-d]pyrimidine Compounds Target Mitochondrial and Cytosolic One-carbon Metabolism with Broad-spectrum Antitumor Efficacy.

Author information

1
Department of Oncology, Wayne State University School of Medicine, and the Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
2
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania.
3
Department of Chemistry/Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey.
4
Department of Chemistry, Indiana University, Bloomington, Indiana.
5
Biochemistry and Molecular Biology, Jilin University, Changchun, Jilin Province, China.
6
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan.
7
Department of Chemistry, Indiana University, Bloomington, Indiana. matherly@karmanos.org gangjee@duq.edu cedann@indiana.edu.
8
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania. matherly@karmanos.org gangjee@duq.edu cedann@indiana.edu.
9
Department of Oncology, Wayne State University School of Medicine, and the Barbara Ann Karmanos Cancer Institute, Detroit, Michigan. matherly@karmanos.org gangjee@duq.edu cedann@indiana.edu.

Abstract

Folate-dependent one-carbon (C1) metabolism is compartmentalized into the mitochondria and cytosol and supports cell growth through nucleotide and amino acid biosynthesis. Mitochondrial C1 metabolism, including serine hydroxymethyltransferase (SHMT) 2, provides glycine, NAD(P)H, ATP, and C1 units for cytosolic biosynthetic reactions, and is implicated in the oncogenic phenotype across a wide range of cancers. Whereas multitargeted inhibitors of cytosolic C1 metabolism, such as pemetrexed, are used clinically, there are currently no anticancer drugs that specifically target mitochondrial C1 metabolism. We used molecular modeling to design novel small-molecule pyrrolo[3,2-d]pyrimidine inhibitors targeting mitochondrial C1 metabolism at SHMT2. In vitro antitumor efficacy was established with the lead compounds (AGF291, AGF320, AGF347) toward lung, colon, and pancreatic cancer cells. Intracellular targets were identified by metabolic rescue with glycine and nucleosides, and by targeted metabolomics using a stable isotope tracer, with confirmation by in vitro assays with purified enzymes. In addition to targeting SHMT2, inhibition of the cytosolic purine biosynthetic enzymes, β-glycinamide ribonucleotide formyltransferase and/or 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase, and SHMT1 was also established. AGF347 generated significant in vivo antitumor efficacy with potential for complete responses against both early-stage and upstage MIA PaCa-2 pancreatic tumor xenografts, providing compelling proof-of-concept for therapeutic targeting of SHMT2 and cytosolic C1 enzymes by this series. Our results establish structure-activity relationships and identify exciting new drug prototypes for further development as multitargeted antitumor agents.

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