title: Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors.
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.
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: 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: 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: Dario
authors.initials: D
authors.lastname: Ballinari
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Bandiera
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: Davide
authors.initials: D
authors.lastname: Carenzi
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: Lucio
authors.initials: L
authors.lastname: Ceriani
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: Alessandra
authors.initials: A
authors.lastname: Cirla
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Maristella
authors.initials: M
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: Cinzia
authors.initials: C
authors.lastname: Cristiani
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Della Vedova
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: Marina
authors.initials: M
authors.lastname: Fasolini
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: Danilo
authors.initials: D
authors.lastname: Mirizzi
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: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.affiliation: Nerviano Medical Sciences S.r.l., Oncology, Viale Pasteur 10, 20014 Nerviano (MI), Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Vianello
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: Daniele
authors.initials: D
authors.lastname: Donati
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: C000596491:5-(2-aminopyrimidin-4-yl)-2-(2-chloro-5-(trifluoromethyl)phenyl)-1H-pyrrole-3-carboxamide; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D053614:Janus Kinase 2
keywords: Anti-cancer agents; JAK2; Myeloproliferative disorders; Protein kinase inhibitor; Tumour cell proliferation inhibition