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

Abstract

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.

SI113, a Specific Inhibitor of the Sgk1 Kinase Activity that Counteracts Cancer Cell Proliferation

“…Interestingly, compounds belonging to the same pyrazolo[3,4-d]pyrimidine library of SI113, showed no apparent sign of toxicity after oral administration for 15 days in mice [39]. …”

Hit Identification and Biological Evaluation of Anticancer Pyrazolopyrimidines Endowed with Anti‐inflammatory Activity

“…Compound 2, the previously reported anticancer agent, [16][17][18][19][20] and the novel parent compound 3, were also well-ranked, with larger differences in the predicted binding affinities of the enantiomers. In particular, compound 3 appeared as interesting as 1 due to their similar binding modes.…”

“…[19] Moreover, some of them showed a significant antiproliferative effect on osteosarcoma cells and are active in a xenograft mouse model of this tumor. [20] On the basis of these reports, and considering the great interest in antitumor agents acting with a dual mechanism (i.e., tyrosine kinase inhibition/anti-inflammatory action), we decided to investigate the potential anti-inflammatory activity of our pyrazolopyrimidines. With this aim, a three-dimensional chemical library containing 423 pyrazolo-and four pyrrolopyrimidines, variously substituted, has been designed and screened in silico against structural models of both COX-1 and COX-2.…”

The Multidisciplinary Management of Osteosarcoma

“…• Small molecule therapy with inhibition of the Src kinase pathway involved in osteoclast activity has been shown to have anti-proliferative and pro-apoptotic activity in osteosarcoma cell lines and xenograft models [75,76]. The orally available Src tyrosine kinase inhibitor AZD0530 is currently being investigated in a phase II clinical trial in osteosarcoma with pulmonary recurrence post-metastasectomy conducted by the Sarcoma Alliance Research through Collaboration…”