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. 2022 Nov;34(11):1437-1452.
doi: 10.1002/chir.23501. Epub 2022 Aug 12.

Stereoselective synthesis of 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as PIM kinase inhibitors inspired from marine alkaloids

Francesco Casuscelli  1   2 , Elena Ardini  1 , Nilla Avanzi  1 , Alessandra Badari  1 , Elena Casale  1 , Teresa Disingrini  1 , Daniele Donati  1 , Antonella Ermoli  1 , Eduard R Felder  1 , Arturo Galvani  1 , Antonella Isacchi  1 , Maria Menichincheri  1 , Marisa Montemartini  1 , Christian Orrenius  1 , Claudia Piutti  2 , Barbara Salom  1 , Gianluca Papeo  1
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Stereoselective synthesis of 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as PIM kinase inhibitors inspired from marine alkaloids

Francesco Casuscelli et al. Chirality. 2022 Nov.

Abstract

We previously demonstrated that natural product-inspired 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones derivatives delivered potent and selective PIM kinases inhibitors however with non-optimal ADME/PK properties and modest oral bioavailability. Herein, we describe a structure-based scaffold decoration and a stereoselective approach to this chemical class. The synthesis, structure-activity relationship studies, chiral analysis, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Compound 20c demonstrated excellent potency on PIM1 and PIM2 with exquisite kinases selectivity and PK properties that efficiently and dose-dependently promoted c-Myc degradation and appear to be promising lead compounds for further development.

Keywords: PIM kinases; anticancer agents; kinase inhibitors; natural product scaffold; pyrrolopyrazinone; stereoselective synthesis.

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References

REFERENCES

    1. Mikkers H, Nawijn M, Allen J, et al. Mice deficient for all PIM kinases display reduced body size and impaired responses to hematopoietic growth factors. Mol Cell Biol. 2004;24:6104-6115. doi:10.1128/MCB.24.13.6104-6115.2004
    1. Nawijn MC, Alendar A, Berns A. For better or for worse: the role of Pim oncogenes in tumorigenesis. Nat Rev Cancer. 2011;11(1):1123-1134. doi:10.1038/nrc2986
    1. Brault L, Gasser C, Bracher F, Huber K, Knapp S, Schwaller J. PIM serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers. Haematologica. 2010;95(6):1004-1015. doi:10.3324/haematol.2009.017079
    1. Blanco-Aparicio C, Carnero A. Pim kinases in cancer: diagnostic, prognostic and treatment opportunities. Biochem Pharmacol. 2013;85(5):629-643. doi:10.1016/j.bcp.2012.09.018
    1. An N, Kraft AS, Kang Y. Abnormal hematopoietic phenotypes in Pim kinase triple knockout mice. J Hematol Oncol. 2013;29(6):12-22. doi:10.1186/1756-8722-6-12

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