Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
The Wohl Drug Discovery Institute of the Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel.
RNA Biol. 2022;19(1):26-43. doi: 10.1080/15476286.2021.2010983. Epub 2021 Dec 31.
Igf2bp1 is an oncofetal RNA binding protein whose expression in numerous types of cancers is associated with upregulation of key pro-oncogenic RNAs, poor prognosis, and reduced survival. Importantly, Igf2bp1 synergizes with mutations in Kras to enhance signalling and oncogenic activity, suggesting that molecules inhibiting Igf2bp1 could have therapeutic potential. Here, we isolate a small molecule that interacts with a hydrophobic surface at the boundary of Igf2bp1 KH3 and KH4 domains, and inhibits binding to Kras RNA. In cells, the compound reduces the level of Kras and other Igf2bp1 mRNA targets, lowers Kras protein, and inhibits downstream signalling, wound healing, and growth in soft agar, all in the absence of any toxicity. This work presents an avenue for improving the prognosis of Igf2bp1-expressing tumours in lung, and potentially other, cancer(s).
Igf2bp1 是一种癌胚 RNA 结合蛋白，其在许多类型癌症中的表达与关键致癌 RNA 的上调、不良预后和生存率降低有关。重要的是，Igf2bp1 与 Kras 突变协同作用，增强信号转导和致癌活性，这表明抑制 Igf2bp1 的分子可能具有治疗潜力。在这里，我们分离到一种小分子，它与 Igf2bp1 KH3 和 KH4 结构域边界的疏水表面相互作用，并抑制与 Kras RNA 的结合。在细胞中，该化合物降低了 Kras 和其他 Igf2bp1 mRNA 靶标水平，降低了 Kras 蛋白，并抑制下游信号转导、伤口愈合和软琼脂中的生长，所有这些都没有任何毒性。这项工作为改善 Igf2bp1 表达肿瘤的预后提供了一种途径，这些肿瘤可能存在于肺部，也可能存在于其他癌症中。
