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3D proteome-wide scale screening and activity evaluation of a new ALKBH5 inhibitor in U87 glioblastoma cell line.
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-12-30 , DOI: 10.1016/j.bmc.2019.115300 Alessio Malacrida 1 , Mirko Rivara 2 , Alessandro Di Domizio 3 , Giacomo Cislaghi 4 , Mariarosaria Miloso 1 , Valentina Zuliani 2 , Gabriella Nicolini 1
Bioorganic & Medicinal Chemistry ( IF 3.3 ) Pub Date : 2019-12-30 , DOI: 10.1016/j.bmc.2019.115300 Alessio Malacrida 1 , Mirko Rivara 2 , Alessandro Di Domizio 3 , Giacomo Cislaghi 4 , Mariarosaria Miloso 1 , Valentina Zuliani 2 , Gabriella Nicolini 1
Affiliation
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The imidazobenzoxazin-5-thione MV1035, synthesized as a new sodium channel blocker, has been tested on tumoral cells that differ for origin and for expressed NaV pool (U87-MG, H460 and A549). In this paper we focus on the effect of MV1035 in reducing U87 glioblastoma cell line migration and invasiveness. Since the effect of this compound on U87-MG cells seemed not dependent on its sodium channel blocking capability, alternative off-target interaction for MV1035 have been identified using SPILLO-PBSS software. This software performs a structure-based in silico screening on a proteome-wide scale, that allows to identify off-target interactions. Among the top-ranked off-targets of MV1035, we focused on the RNA demethylase ALKBH5 enzyme, known for playing a key role in cancer. In order to prove the effect of MV1035 on ALKBH5 in vitro coincubation of MV1035 and ALKBH5 has been performed demonstrating a consequent increase of N6-methyladenosine (m6A) RNA. To further validate the pathway involving ALKBH5 inhibition by MV1035 in U87-MG reduced migration and invasiveness, we evaluated CD73 as possible downstream protein. CD73 is an extrinsic protein involved in the generation of adenosine and is overexpressed in several tumors including glioblastoma. We have demonstrated that treating U87-MG with MV1035, CD73 protein expression was reduced without altering CD73 transcription. Our results show that MV1035 is able to significantly reduce U87 cell line migration and invasiveness inhibiting ALKBH5, an RNA demethylase that can be considered an interesting target in fighting glioblastoma aggressiveness. Our data encourage to further investigate the MV1035 inhibitory effect on glioblastoma.
中文翻译：
U87胶质母细胞瘤细胞系中新型ALKBH5抑制剂的3D蛋白质组规模筛选和活性评估。
合成为新型钠通道阻滞剂的咪唑并苯并恶嗪-5-硫酮MV1035已在肿瘤细胞上进行了测试，这些肿瘤细胞的来源和表达的Nav池均不同（U87-MG，H460和A549）。在本文中，我们集中于MV1035在减少U87胶质母细胞瘤细胞系迁移和侵袭性中的作用。由于该化合物对U87-MG细胞的作用似乎不依赖于其钠通道阻滞能力，因此使用SPILLO-PBSS软件已经确定了MV1035的其他脱靶相互作用。该软件在整个蛋白质组范围内执行基于结构的计算机模拟筛选，从而可以识别脱靶相互作用。在MV1035的最高脱靶位中，我们集中于RNA脱甲基酶ALKBH5酶，该酶以在癌症中起关键作用而闻名。为了证明MV1035对ALKBH5的作用，已经进行了MV1035和ALKBH5的体外共培养，证明了随之而来的N6-甲基腺苷（m6A）RNA的增加。为了进一步验证MV1035在U87-MG中抑制ALKBH5抑制的途径降低了迁移和侵袭性，我们将CD73评估为可能的下游蛋白。CD73是一种与腺苷产生有关的外在蛋白，在包括胶质母细胞瘤在内的多种肿瘤中过表达。我们已经证明用MV1035处理U87-MG，在不改变CD73转录的情况下减少了CD73蛋白的表达。我们的结果表明，MV1035能够显着降低U87细胞系迁移和侵袭性，抑制ALKBH5（一种被认为是对抗胶质母细胞瘤侵袭的有趣靶标的RNA脱甲基酶）。
更新日期：2019-12-30
中文翻译：
U87胶质母细胞瘤细胞系中新型ALKBH5抑制剂的3D蛋白质组规模筛选和活性评估。
合成为新型钠通道阻滞剂的咪唑并苯并恶嗪-5-硫酮MV1035已在肿瘤细胞上进行了测试，这些肿瘤细胞的来源和表达的Nav池均不同（U87-MG，H460和A549）。在本文中，我们集中于MV1035在减少U87胶质母细胞瘤细胞系迁移和侵袭性中的作用。由于该化合物对U87-MG细胞的作用似乎不依赖于其钠通道阻滞能力，因此使用SPILLO-PBSS软件已经确定了MV1035的其他脱靶相互作用。该软件在整个蛋白质组范围内执行基于结构的计算机模拟筛选，从而可以识别脱靶相互作用。在MV1035的最高脱靶位中，我们集中于RNA脱甲基酶ALKBH5酶，该酶以在癌症中起关键作用而闻名。为了证明MV1035对ALKBH5的作用，已经进行了MV1035和ALKBH5的体外共培养，证明了随之而来的N6-甲基腺苷（m6A）RNA的增加。为了进一步验证MV1035在U87-MG中抑制ALKBH5抑制的途径降低了迁移和侵袭性，我们将CD73评估为可能的下游蛋白。CD73是一种与腺苷产生有关的外在蛋白，在包括胶质母细胞瘤在内的多种肿瘤中过表达。我们已经证明用MV1035处理U87-MG，在不改变CD73转录的情况下减少了CD73蛋白的表达。我们的结果表明，MV1035能够显着降低U87细胞系迁移和侵袭性，抑制ALKBH5（一种被认为是对抗胶质母细胞瘤侵袭的有趣靶标的RNA脱甲基酶）。
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