Identification of a novel pyrazolo[3,4-d]pyrimidine able to inhibit cell proliferation of a human osteogenic sarcoma in vitro and in a xenograft model in mice.
New pyrazolo[3,4-d]pyrimidines were synthesized and found to inhibit Src phosphorylation in a cell-free assay. Some of them significantly reduced the growth of human osteogenic sarcoma (SaOS-2) cells. The best compound, in terms of inhibitory properties toward both Src and SaOS-2 cells, was further investigated and found to reduce bone resorption when used to treat mouse osteoclasts, without interfering with normal osteoblast growth. Moreover, its metabolic stability prompted its study on a human SaOS-2 xenograft tumor model in nude mice, where the compound reduced significantly both the volume and weight of the tumor. These experimental findings make the new compound an interesting hit in the field of bone-related diseases.
Manetti
Fabrizio
F
Dipartimento Farmaco Chimico Tecnologico, Università degli Studi di Siena, Siena, Italy.
Santucci
Annalisa
A
Locatelli
Giada A
GA
Maga
Giovanni
G
Spreafico
Adriano
A
Serchi
Tommaso
T
Orlandini
Maurizio
M
Bernardini
Giulia
G
Caradonna
Nicola P
NP
Spallarossa
Andrea
A
Brullo
Chiara
C
Schenone
Silvia
S
Bruno
Olga
O
Ranise
Angelo
A
Bondavalli
Francesco
F
Hoffmann
Oskar
O
Bologna
Mauro
M
Angelucci
Adriano
A
Botta
Maurizio
M
D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000473:pathology; D001862:Bone Resorption / Q000517:prevention & control; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010006:Osteoblasts / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects; D012516:Osteosarcoma / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D011720:Pyrazoles; D011743:Pyrimidines; D019061:src-Family Kinases