Department of Pharmacy, University of Genoa, Viale Benedetto XV 3, 16132 Genoa, Italy.
Int J Mol Sci. 2024 Jan 23;25(3):1398. doi: 10.3390/ijms25031398.
In the last decade, many small molecules, usually characterized by heterocyclic scaffolds, have been designed and synthesized as tyrosine kinase inhibitors (TKIs). Among them, several compounds have been tested at preclinical and clinical levels to treat glioblastoma multiforme (GBM). GBM is the most common and aggressive type of cancer originating in the brain and has an unfavorable prognosis, with a median survival of 15-16 months and a 5-year survival rate of 5%. Despite recent advances in treating GBM, it represents an incurable disease associated with treatment resistance and high recurrence rates. For these reasons, there is an urgent need for the development of new pharmacological agents to fight this malignancy. In this review, we reported the compounds published in the last five years, which showed promising activity in GBM preclinical models acting as TKIs. We grouped the compounds based on the targeted kinase: first, we reported receptor TKIs and then, cytoplasmic and peculiar kinase inhibitors. For each small molecule, we included the chemical structure, and we schematized the interaction with the target for some representative compounds with the aim of elucidating the mechanism of action. Finally, we cited the most relevant clinical trials.
在过去的十年中，已经设计并合成了许多小分子，这些小分子通常具有杂环支架，被用作酪氨酸激酶抑制剂（TKIs）。其中，一些化合物已在临床前和临床水平进行了测试，以治疗多形性胶质母细胞瘤（GBM）。GBM 是起源于大脑的最常见和侵袭性的癌症，预后不良，中位生存期为 15-16 个月，5 年生存率为 5%。尽管最近在治疗 GBM 方面取得了进展，但它仍然是一种无法治愈的疾病，与治疗耐药和高复发率有关。出于这些原因，迫切需要开发新的药理学制剂来对抗这种恶性肿瘤。在这篇综述中，我们报道了过去五年中发表的在 GBM 临床前模型中表现出有希望的活性的化合物，这些化合物作为 TKIs。我们根据靶向激酶对化合物进行了分类：首先报道了受体 TKIs，然后是细胞质和特殊激酶抑制剂。对于每个小分子，我们都包括了化学结构，并为一些代表性化合物绘制了与靶标的相互作用图，旨在阐明作用机制。最后，我们引用了最相关的临床试验。
