Tapcin, an In Vivo Active Dual Topoisomerase I/II Inhibitor Discovered by Synthetic Bioinformatic Natural Product (Syn-BNP)-Coupled Metagenomics
Dr. Zongqiang Wang
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
These authors contributed equally to this work.
Search for more papers by this authorDr. Amanda Kasper
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
These authors contributed equally to this work.
Search for more papers by this authorDr. Mai Takahashi
Laboratory of Systems Cancer Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorDr. Adrian Morales Amador
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorDr. Abir Bhattacharjee
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorDr. Jingbo Kan
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorDr. Yozen Hernandez
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorMelinda Ternei
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorCorresponding Author
Prof. Sean F. Brady
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorDr. Zongqiang Wang
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
These authors contributed equally to this work.
Search for more papers by this authorDr. Amanda Kasper
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
These authors contributed equally to this work.
Search for more papers by this authorDr. Mai Takahashi
Laboratory of Systems Cancer Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorDr. Adrian Morales Amador
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorDr. Abir Bhattacharjee
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorDr. Jingbo Kan
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorDr. Yozen Hernandez
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorMelinda Ternei
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorCorresponding Author
Prof. Sean F. Brady
Laboratory of Genetically Encoded Small Molecules, The Rockefeller University, 1230 York Avenue, New York, NY 10065 USA
Search for more papers by this authorAbstract
DNA topoisomerases are attractive targets for anticancer agents. Dual topoisomerase I/II inhibitors are particularly appealing due to their reduced rates of resistance. A number of therapeutically relevant topoisomerase inhibitors are bacterial natural products. Mining the untapped chemical diversity encoded by soil microbiomes presents an opportunity to identify additional natural topoisomerase inhibitors. Here we couple metagenome mining, bioinformatic structure prediction algorithms, and chemical synthesis to produce the dual topoisomerase inhibitor tapcin. Tapcin is a mixed p-aminobenzoic acid (PABA)-thiazole with a rare tri-thiazole substructure and picomolar antiproliferative activity. Tapcin reduced colorectal adenocarcinoma HT-29 cell proliferation and tumor volume in mouse hollow fiber and xenograft models, respectively. In both studies it showed similar activity to the clinically used topoisomerase I inhibitor irinotecan. The study suggests that the interrogation of soil microbiomes using synthetic bioinformatic natural product methods has the potential to be a rewarding strategy for identifying potent, biomedically relevant, antiproliferative agents.
Open Research
Data Availability Statement
The data that support the findings of this study are openly available in ncbi at https://www.ncbi.nlm.nih.gov, reference number 950198.
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