title: Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders.
abstract: Compound 1, a hit from the screening of our chemical collection displaying activity against JAK2, was deconstructed for SAR analysis into three regions, which were explored. A series of compounds was synthesized leading to the identification of the potent and orally bioavailable JAK2 inhibitor 16 (NMS-P830), which showed an encouraging tumour growth inhibition in SET-2 xenograft tumour model, with evidence for JAK2 pathway suppression demonstrated by in vivo pharmacodynamic effects.
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy. Electronic address: gabriella.brasca@nervianoms.com.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Brasca
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Gnocchi
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Marcella
authors.initials: M
authors.lastname: Nesi
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Amboldi
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Nilla
authors.initials: N
authors.lastname: Avanzi
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Jay
authors.initials: J
authors.lastname: Bertrand
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Bindi
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Canevari
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Casero
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Ciomei
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Colombo
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Cribioli
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fachin
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Eduard R
authors.initials: ER
authors.lastname: Felder
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Galvani
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Isacchi
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Motto
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Achille
authors.initials: A
authors.lastname: Panzeri
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Donati
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007947:Leukemia, Megakaryoblastic, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D055016:Megakaryocyte Progenitor Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C507924:JAK2 protein, human; D053614:Janus Kinase 2
keywords: Anti-cancer agents; JAK2; Myeloproliferative disorders; Protein kinase inhibitor; Tumour cell proliferation inhibition