title: NMS-P937, a 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivative as potent and selective Polo-like kinase 1 inhibitor.
abstract: As part of our drug discovery effort, we identified and developed 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as PLK1 inhibitors. We now report the optimization of this class that led to the identification of NMS-P937, a potent, selective and orally available PLK1 inhibitor. Also, in order to understand the source of PLK1 selectivity, we determined the crystal structure of PLK1 with NMS-P937. The compound was active in vivo in HCT116 xenograft model after oral administration and is presently in Phase I clinical trials evaluation.
authors.affiliation: Nerviano Medical Sciences srl, Business Unit Oncology, Viale Pasteur 10, 20014 Nerviano, MI, Italy. italo.beria@nervianoms.com
authors.forename: Italo
authors.initials: I
authors.lastname: Beria
authors.forename: Roberto T
authors.initials: RT
authors.lastname: Bossi
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Brasca
authors.forename: Michele
authors.initials: M
authors.lastname: Caruso
authors.forename: Walter
authors.initials: W
authors.lastname: Ceccarelli
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fachin
authors.forename: Marina
authors.initials: M
authors.lastname: Fasolini
authors.forename: Barbara
authors.initials: B
authors.lastname: Forte
authors.forename: Francesco
authors.initials: F
authors.lastname: Fiorentini
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Daniele
authors.initials: D
authors.lastname: Pezzetta
authors.forename: Helena
authors.initials: H
authors.lastname: Posteri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Scolaro
authors.forename: Stefania
authors.initials: S
authors.lastname: Re Depaolini
authors.forename: Barbara
authors.initials: B
authors.lastname: Valsasina
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D049109:Cell Proliferation / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D020128:Inhibitory Concentration 50; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011799:Quinazolines; D000097869:Polo-Like Kinase 1; C560415:NMS P937