Articolo in rivista, 2023, ENG, 10.3390/ph16070958

Identification and Biological Characterization of the Pyrazolo[3,4-<i>d</i>]pyrimidine Derivative SI388 Active as Src Inhibitor

Contadini C, Cirotti C, Carbone A, Norouzi M, Cianciusi A, Crespan E, Perini C, Maga G, Barilà D, Musumeci F, Schenone S

Laboratory of Cell Signaling, IRCCS-Fondazione Santa Lucia, 00179 Rome, Italy; Department of Biology, University of Rome "Tor Vergata", 00133 Rome, Italy; Department of Pharmacy, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy; Institute of Molecular Genetics (IGM), IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy.

Src is a non-receptor tyrosine kinase (TK) whose involvement in cancer, including glioblastoma (GBM), has been extensively demonstrated. In this context, we started from our in-house library of pyrazolo[3,4-d]pyrimidines that are active as Src and/or Bcr-Abl TK inhibitors and performed a lead optimization study to discover a new generation derivative that is suitable for Src kinase targeting. We synthesized a library of 19 compounds, 2a-s. Among these, compound 2a (SI388) was identified as the most potent Src inhibitor. Based on the cell-free results, we investigated the effect of SI388 in 2D and 3D GBM cellular models. Interestingly, SI388 significantly inhibits Src kinase, and therefore affects cell viability, tumorigenicity and enhances cancer cell sensitivity to ionizing radiation.

Pharmaceuticals (Basel) 16 (7)

Keywords

Src kinase, glioblastoma, radiotherapy resistance, pyrazolo[3, 4-d]pyrimidines

CNR authors

Maga Giovanni, Crespan Emmanuele

CNR institutes

IGM – Istituto di genetica molecolare "Luigi Luca Cavalli Sforza"