Galimberti Chiara, Piepoli Tiziana, Letari Ornella, Artusi Roberto, Persiani Stefano, Caselli Gianfranco, Rovati Lucio C
Rottapharm Biotech Srl Monza, Italy.
PhD Program in Neuroscience, University of Milano - Bicocca Monza, Italy.
Am J Cancer Res. 2021 Jul 15;11(7):3558-3574. eCollection 2021.
Glioblastoma multiforme (GBM) is the most malignant primary brain cancer. Despite aggressive treatments currently there is no cure for GBM. Many challenges should be considered for the development of new therapeutical agents for glioblastoma, including appropriate target selectivity and pharmacokinetics. Several mutations and alterations of key cellular pathways including tyrosine kinases (TKs) are involved in malignant transformation and tumor progression. Thus, the targeting of multiple pathways and the development of innovative combination drug regimens is expected to yield improved therapies. Moreover, the abilities to cross the blood-brain barrier (BBB) reaching effective concentrations in brain and to remain into this tissue avoiding the effects of efflux transporters are also critical issues in the development of new therapeutics for GBM. CR13626 is a novel brain penetrant small molecule able to potently inhibit in vitro the activity of EGFR, VEGFR2 (aka KDR), Fyn, Yes, Lck, HGK (aka MAP4K4) and RET kinases relevant for GBM development. CR13626 shows good oral bioavailability (72%) and relevant brain penetration (brain/plasma ratio of 1.4). In an orthotopic xenograft glioblastoma mouse model, oral treatment with CR13626 results in a time-dependent reduction of tumor growth, leading to a significant increase of animal survival. The unique properties of CR13626 warrant its further investigation as a potential new drug candidate in glioblastoma.
多形性胶质母细胞瘤（GBM）是最恶性的原发性脑癌。尽管目前采用了积极的治疗方法，但GBM仍无法治愈。在开发用于胶质母细胞瘤的新型治疗药物时，应考虑许多挑战，包括适当的靶点选择性和药代动力学。包括酪氨酸激酶（TKs）在内的几个关键细胞通路的突变和改变与恶性转化和肿瘤进展有关。因此，针对多种通路以及开发创新的联合用药方案有望带来更好的治疗效果。此外，穿过血脑屏障（BBB）并在脑内达到有效浓度，以及在该组织中留存以避免外排转运体的影响，这些能力也是开发GBM新疗法的关键问题。CR13626是一种新型的具有脑渗透性的小分子，能够在体外有效抑制与GBM发展相关的EGFR、VEGFR2（又名KDR）、Fyn、Yes、Lck、HGK（又名MAP4K4）和RET激酶的活性。CR13626具有良好的口服生物利用度（72%）和显著的脑渗透性（脑/血浆比率为1.4）。在原位异种移植胶质母细胞瘤小鼠模型中，用CR13626进行口服治疗可使肿瘤生长随时间减少，从而显著提高动物存活率。CR13626的独特特性使其有理由作为胶质母细胞瘤潜在的新药候选物进行进一步研究。
