Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors

  • Bioorg Med Chem. 2014 Sep 1;22(17):4998-5012. doi: 10.1016/j.bmc.2014.06.025.
Maria Gabriella Brasca  1 ,  Marcella Nesi  2 ,  Nilla Avanzi  2 ,  Dario Ballinari  2 ,  Tiziano Bandiera  2 ,  Jay Bertrand  2 ,  Simona Bindi  2 ,  Giulia Canevari  2 ,  Davide Carenzi  2 ,  Daniele Casero  2 ,  Lucio Ceriani  2 ,  Marina Ciomei  2 ,  Alessandra Cirla  2 ,  Maristella Colombo  2 ,  Sabrina Cribioli  2 ,  Cinzia Cristiani  2 ,  Franco Della Vedova  2 ,  Gabriele Fachin  2 ,  Marina Fasolini  2 ,  Eduard R Felder  2 ,  Arturo Galvani  2 ,  Antonella Isacchi  2 ,  Danilo Mirizzi  2 ,  Ilaria Motto  2 ,  Achille Panzeri  2 ,  Enrico Pesenti  2 ,  Paola Vianello  2 ,  Paola Gnocchi  2 ,  Daniele Donati  2
Affiliations
  • 1. Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address: [email protected].
  • 2. Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
PMID: 25009002 DOI: 10.1016/j.bmc.2014.06.025
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.

Keywords
Anti-cancer agents; JAK2; Myeloproliferative disorders; Protein kinase inhibitor; Tumour cell proliferation inhibition.
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