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.
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.
Beria
Italo
I
Nerviano Medical Sciences Srl, Oncology, Viale Pasteur 10, 20014 Nerviano, (Mi), Italy. italo.beria@nervianoms.com
Ballinari
Dario
D
Bertrand
Jay Aaron
JA
Borghi
Daniela
D
Bossi
Roberto Tiberio
RT
Brasca
Maria Gabriella
MG
Cappella
Paolo
P
Caruso
Michele
M
Ceccarelli
Walter
W
Ciavolella
Antonella
A
Cristiani
Cinzia
C
Croci
Valter
V
De Ponti
Anna
A
Fachin
Gabriele
G
Ferguson
Ronald Dale
RD
Lansen
Jacqueline
J
Moll
Jurgen Karl
JK
Pesenti
Enrico
E
Posteri
Helena
H
Perego
Rita
R
Rocchetti
Maurizio
M
Storici
Paola
P
Volpi
Daniele
D
Valsasina
Barbara
B
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
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