2. Academic Validation
  3. Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases

Discovery and optimization of pyrrolo[1,2-a]pyrazinones leads to novel and selective inhibitors of PIM kinases

  • Bioorg Med Chem. 2013 Dec 1;21(23):7364-80. doi: 10.1016/j.bmc.2013.09.054.
Francesco Casuscelli 1,  Elena Ardini,  Nilla Avanzi,  Elena Casale,  Giovanni Cervi,  Matteo D'Anello,  Daniele Donati,  Daniela Faiardi,  Ronald D Ferguson,  Gianpaolo Fogliatto,  Arturo Galvani,  Aurelio Marsiglio,  Danilo G Mirizzi,  Marisa Montemartini,  Christian Orrenius,  Gianluca Papeo,  Claudia Piutti,  Barbara Salom,  Eduard R Felder
Affiliations

Affiliation

  • 1 Oncology, Nerviano Medical Sciences, viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address: [email protected].
PMID: 24139169 DOI: 10.1016/j.bmc.2013.09.054
Abstract

A novel series of Pim inhibitors was derived from a combined effort in natural product-inspired library generation and screening. The novel pyrrolo[1,2-a]pyrazinones initial hits are inhibitors of Pim isoforms with IC50 values in the low micromolar range. The application of a rational optimization strategy, guided by the determination of the crystal structure of the complex in the kinase domain of PIM1 with compound 1, led to the discovery of compound 15a, which is a potent Pim kinases inhibitor exhibiting excellent selectivity against a large panel of kinases, representative of each family. The synthesis, structure-activity relationship studies, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Furthermore, the cellular activities including inhibition of cell growth and modulation of downstream targets are also described.

Keywords

Anti-cancer agents; Kinase selectivity; Natural product scaffold; PIM kinases; Pyrrolopyrazinone.

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