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

TitleNovel Pyrrolo[3,2-]pyrimidine Compounds Target Mitochondrial and Cytosolic One-carbon Metabolism with Broad-spectrum Antitumor Efficacy.
Publication TypeJournal Article
Year of Publication2019
AuthorsDekhne, AS, Shah, K, Ducker, GS, Katinas, JM, Wong-Roushar, J, Nayeen, MJunayed, Doshi, A, Ning, C, Bao, X, Frühauf, J, Liu, J, Wallace-Povirk, A, O'Connor, C, Dzinic, SH, White, K, Kushner, J, Kim, S, Hüttemann, M, Polin, L, Rabinowitz, JD, Li, J, Hou, Z, Dann, CE, Gangjee, A, Matherly, LH
JournalMol Cancer Ther
Volume18
Issue10
Pagination1787-1799
Date Published2019 10
ISSN1538-8514
KeywordsAnimals, Antineoplastic Agents, Biosynthetic Pathways, Carbon, Cell Line, Tumor, CHO Cells, Cricetinae, Cricetulus, Cytosol, Female, Inhibitory Concentration 50, Metabolomics, Mice, SCID, Mitochondria, Purines, Pyrimidines, Pyrroles, Xenograft Model Antitumor Assays
Abstract

<p>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-]pyrimidine inhibitors targeting mitochondrial C1 metabolism at SHMT2. antitumor efficacy was established with the lead compounds (, , ) 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 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. generated significant 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.</p>

DOI10.1158/1535-7163.MCT-19-0037
Alternate JournalMol. Cancer Ther.
PubMed ID31289137
PubMed Central IDPMC6774887
Grant ListR01 CA152316 / CA / NCI NIH HHS / United States
R00 CA215307 / CA / NCI NIH HHS / United States
R01 CA076641 / CA / NCI NIH HHS / United States
R01 CA163591 / CA / NCI NIH HHS / United States
DP1 DK113643 / DK / NIDDK NIH HHS / United States
R01 CA053535 / CA / NCI NIH HHS / United States
R01 CA166711 / CA / NCI NIH HHS / United States
F31 CA243215 / CA / NCI NIH HHS / United States
K99 CA215307 / CA / NCI NIH HHS / United States
F30 CA228221 / CA / NCI NIH HHS / United States
T32 CA009531 / CA / NCI NIH HHS / United States
P30 CA022453 / CA / NCI NIH HHS / United States