title: Identification of 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline derivatives as a new class of orally and selective Polo-like kinase 1 inhibitors.
abstract: Polo-like kinase 1 (Plk1) is a fundamental regulator of mitotic progression whose overexpression is often associated with oncogenesis and therefore is recognized as an attractive therapeutic target in the treatment of proliferative diseases. Here we discuss the structure-activity relationship of the 4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline class of compounds that emerged from a high throughput screening (HTS) campaign as potent inhibitors of Plk1 kinase. Furthermore, we describe the discovery of 49, 8-{[2-methoxy-5-(4-methylpiperazin-1-yl)phenyl]amino}-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, as a highly potent and specific ATP mimetic inhibitor of Plk1 (IC(50) = 0.007 microM) as well as its crystal structure in complex with the methylated Plk1(36-345) construct. Compound 49 was active in cell proliferation against different tumor cell lines with IC(50) values in the submicromolar range and active in vivo in the HCT116 xenograft model where it showed 82% tumor growth inhibition after repeated oral administration.
authors.affiliation: Nerviano Medical Sciences Srl, Oncology, Viale Pasteur 10, 20014 Nerviano, (Mi), Italy. italo.beria@nervianoms.com
authors.forename: Italo
authors.initials: I
authors.lastname: Beria
authors.forename: Dario
authors.initials: D
authors.lastname: Ballinari
authors.forename: Jay Aaron
authors.initials: JA
authors.lastname: Bertrand
authors.forename: Daniela
authors.initials: D
authors.lastname: Borghi
authors.forename: Roberto Tiberio
authors.initials: RT
authors.lastname: Bossi
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Brasca
authors.forename: Paolo
authors.initials: P
authors.lastname: Cappella
authors.forename: Michele
authors.initials: M
authors.lastname: Caruso
authors.forename: Walter
authors.initials: W
authors.lastname: Ceccarelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Ciavolella
authors.forename: Cinzia
authors.initials: C
authors.lastname: Cristiani
authors.forename: Valter
authors.initials: V
authors.lastname: Croci
authors.forename: Anna
authors.initials: A
authors.lastname: De Ponti
authors.forename: Gabriele
authors.initials: G
authors.lastname: Fachin
authors.forename: Ronald Dale
authors.initials: RD
authors.lastname: Ferguson
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Lansen
authors.forename: Jurgen Karl
authors.initials: JK
authors.lastname: Moll
authors.forename: Enrico
authors.initials: E
authors.lastname: Pesenti
authors.forename: Helena
authors.initials: H
authors.lastname: Posteri
authors.forename: Rita
authors.initials: R
authors.lastname: Perego
authors.forename: Maurizio
authors.initials: M
authors.lastname: Rocchetti
authors.forename: Paola
authors.initials: P
authors.lastname: Storici
authors.forename: Daniele
authors.initials: D
authors.lastname: Volpi
authors.forename: Barbara
authors.initials: B
authors.lastname: Valsasina
mesh_terms: D000255:Adenosine Triphosphate; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018716:Molecular Mimicry; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays; D000097869:Polo-Like Kinase 1
chemical_list: D000255:Adenosine Triphosphate; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000097869:Polo-Like Kinase 1