Greco Chiara, Taresco Vincenzo, Pearce Amanda K, Vasey Catherine E, Smith Stuart, Rahman Ruman, Alexander Cameron, Cavanagh Robert J, Musumeci Francesca, Schenone Silvia
Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132 Genoa, Italy.
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
ACS Med Chem Lett. 2020 Feb 13;11(5):657-663. doi: 10.1021/acsmedchemlett.9b00530. eCollection 2020 May 14.
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor. Residual cells at the tumor margin are responsible for up to 85% of GBM recurrences after standard treatment. Despite this evidence, the identification of compounds active on this cell population is still an underexplored field. Herein, starting from the knowledge that kinases are implicated in GBM, we evaluated three in-house pyrazolo[3,4-]pyrimidines active as Src, Fyn, and SGK1 kinase inhibitors against patient derived cell lines from either the invasive region or contrast-enhanced core of GBM. We identified our Src inhibitor, SI306, as a promising lead compound for eradicating invasive GBM cells. Furthermore, aiming at the development of a feasible oral treatment for GBM, we performed a formulation study using 2D inkjet printing to generate soluble polymer-drug dispersions. Overall, this study led to the identification of a set of polymer-formulated pyrazolo[3,4-]pyrimidine kinase inhibitors as promising candidates for GBM preclinical efficacy studies.
多形性胶质母细胞瘤（GBM）是最具侵袭性的原发性脑肿瘤。肿瘤边缘的残留细胞在标准治疗后导致高达85%的GBM复发。尽管有这一证据，但针对这一细胞群体具有活性的化合物的鉴定仍是一个未被充分探索的领域。在此，基于激酶与GBM有关的认识，我们评估了三种作为Src、Fyn和SGK1激酶抑制剂的内部吡唑并[3,4 -]嘧啶，用于针对来自GBM侵袭区域或增强扫描核心的患者来源细胞系。我们确定我们的Src抑制剂SI306是一种用于根除侵袭性GBM细胞的有前景的先导化合物。此外，为了开发一种可行的GBM口服治疗方法，我们使用二维喷墨打印进行了制剂研究，以生成可溶性聚合物 - 药物分散体。总体而言，这项研究导致鉴定出一组聚合物制剂的吡唑并[3,4 -]嘧啶激酶抑制剂，作为GBM临床前疗效研究的有前景的候选药物。
