Novel imidazopyrimidines-based molecules induce tetramerization of tumor pyruvate kinase M2 and exhibit potent antiproliferative profile

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2022
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Patel, Sagarkumar
Pulugu, Priyanka
Kumar, Prasoon
Jain, Alok
Shard, Amit
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Discovery of novel and potent lead molecules for the specific therapeutic targets by de novo drug design is still in infancy. Here, we disclose the unprecedented development of imidazopyri(mi)dine-based tumor pyruvate kinase M2 (PKM2) modulators by subsequent link and grow strategy. The most potent modulator 15n acts as a PKM2 activator with an AC50 of 90 nM, with considerable cancer cell-selectivity and membrane-permeability. NMR metabolomics studies also revealed that treatment with 15n results in diminution in lactate concentrations in MCF-7 cells. 15n binds to a previously reported site at PKM2 adjacent to the interface of two monomers. In molecular dynamics (MD) simulation studies, it was observed that 15n stabilizes the PKM2 at the dimeric interface, assisting in the formation of a biologically active tetramer conformation. 15n was also screened on MCF-7 breast cancer cell lines grown on 3-D scaffolds, and the results exhibited better anticancer potential compared to control, paving the way for future clinical studies.

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540 Chemie
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Pyruvate kinase M2 modulator, Imidazopyrimidine, Imidazopyridine, anticancer, NMR metabolomics
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ISO 690PATEL, Sagarkumar, Christoph GLOBISCH, Priyanka PULUGU, Prasoon KUMAR, Alok JAIN, Amit SHARD, 2022. Novel imidazopyrimidines-based molecules induce tetramerization of tumor pyruvate kinase M2 and exhibit potent antiproliferative profile. In: European Journal of Pharmaceutical Sciences. Elsevier. 2022, 170, 106112. ISSN 0928-0987. eISSN 1879-0720. Available under: doi: 10.1016/j.ejps.2021.106112
BibTex
@article{Patel2022Novel-57473,
  year={2022},
  doi={10.1016/j.ejps.2021.106112},
  title={Novel imidazopyrimidines-based molecules induce tetramerization of tumor pyruvate kinase M2 and exhibit potent antiproliferative profile},
  volume={170},
  issn={0928-0987},
  journal={European Journal of Pharmaceutical Sciences},
  author={Patel, Sagarkumar and Globisch, Christoph and Pulugu, Priyanka and Kumar, Prasoon and Jain, Alok and Shard, Amit},
  note={Article Number: 106112}
}
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