Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors

Maria Gabriella Brasca, Marcella Nesi, Nilla Avanzi, Dario Ballinari, Tiziano Bandiera, Jay Bertrand, Simona Bindi, Giulia Canevari, Davide Carenzi, Daniele Casero, Lucio Ceriani, Marina Ciomei, Alessandra Cirla, Maristella Colombo, Sabrina Cribioli, Cinzia Cristiani, Franco Della Vedova, Gabriele Fachin, Marina Fasolini, Eduard R. FelderArturo Galvani, Antonella Isacchi, Danilo Mirizzi, Ilaria Motto, Achille Panzeri, Enrico Pesenti, Paola Vianello, Paola Gnocchi, Daniele Donati

Research output: Contribution to journalArticlepeer-review

Abstract

We report herein the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors. Optimization of the series led to the identification of the potent and orally bioavailable JAK2 inhibitor 28 (NMS-P953). Compound 28 displayed significant tumour growth inhibition in SET-2 xenograft tumour model, with a mechanism of action confirmed in vivo by typical modulation of known biomarkers, and with a favourable pharmacokinetic and safety profile.

Original languageEnglish
Pages (from-to)4998-5012
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume22
Issue number17
DOIs
Publication statusPublished - Sep 1 2014

Keywords

  • Anti-cancer agents
  • JAK2
  • Myeloproliferative disorders
  • Protein kinase inhibitor
  • Tumour cell proliferation inhibition

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Molecular Biology
  • Molecular Medicine
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Medicine(all)

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