Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61.
Chemical, computational and functional insights into the chemical stability of the Hedgehog pathway inhibitor GANT61.
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DOI：
10.1080/14756366.2017.1419221
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发表时间：
2018-12
影响因子：
5.6
通讯作者：
Ghirga F
中科院分区：
文献类型：
--
作者：
Calcaterra A;Iovine V;Botta B;Quaglio D;D'Acquarica I;Ciogli A;Iazzetti A;Alfonsi R;Lospinoso Severini L;Infante P;Di Marcotullio L;Mori M;Ghirga F
这项工作旨在阐明GANT 61水解的机制和动力学，GANT 61是第一个也是最广泛使用的Hedgehog（Hh）信号通路抑制剂，靶向胶质瘤相关癌基因同源物（Gli）蛋白，并确认其生物活性形式的化学性质。GANT 61在生理条件下稳定性差，并迅速水解成醛类物质（GANT 61-A）和二胺衍生物（GANT 61-D），醛类物质（GANT 61-A）缺乏针对Hh信号传导的生物活性，二胺衍生物（GANT 61-D）显示出对Gli介导的转录的抑制。在这里，我们结合化学合成，NMR光谱，分析研究，分子建模和功能细胞测定来验证GANT 61水解途径。我们的研究结果表明，GANT 61-D是NIH 3 T3 Shh-Light II细胞和SuFu−/−小鼠胚胎成纤维细胞中GANT 61的生物活性形式，并阐明了GANT 61-D与Gli 1结合的结构要求。这项研究为设计具有更高效力和化学稳定性的GANT 61衍生物铺平了道路。
This work aims at elucidating the mechanism and kinetics of hydrolysis of GANT61, the first and most-widely used inhibitor of the Hedgehog (Hh) signalling pathway that targets Glioma-associated oncogene homologue (Gli) proteins, and at confirming the chemical nature of its bioactive form. GANT61 is poorly stable under physiological conditions and rapidly hydrolyses into an aldehyde species (GANT61-A), which is devoid of the biological activity against Hh signalling, and a diamine derivative (GANT61-D), which has shown inhibition of Gli-mediated transcription. Here, we combined chemical synthesis, NMR spectroscopy, analytical studies, molecular modelling and functional cell assays to characterise the GANT61 hydrolysis pathway. Our results show that GANT61-D is the bioactive form of GANT61 in NIH3T3 Shh-Light II cells and SuFu−/− mouse embryonic fibroblasts, and clarify the structural requirements for GANT61-D binding to Gli1. This study paves the way to the design of GANT61 derivatives with improved potency and chemical stability.
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DOI：
10.1016/s0021-9673(00)96972-3
发表时间：
1990-01-19
期刊：
JOURNAL OF CHROMATOGRAPHY
影响因子：
--
作者：
ALPERT, AJ
通讯作者：
ALPERT, AJ
DOI：
10.15252/embj.201489213
发表时间：
2015-01-13
期刊：
The EMBO journal
影响因子：
--
作者：
Infante P;Mori M;Alfonsi R;Ghirga F;Aiello F;Toscano S;Ingallina C;Siler M;Cucchi D;Po A;Miele E;D'Amico D;Canettieri G;De Smaele E;Ferretti E;Screpanti I;Uccello Barretta G;Botta M;Botta B;Gulino A;Di Marcotullio L
通讯作者：
Di Marcotullio L
影响因子：
3.1
作者：
Iovine, Valentina;Mori, Mattia;Botta, Bruno
通讯作者：
Botta, Bruno
影响因子：
56.9
作者：
Berman, DM;Karhadkar, SS;Beachy, PA
通讯作者：
Beachy, PA
影响因子：
3.2
作者：
Cau, Ylenia;Mori, Mattia;Botta, Maurizio
通讯作者：
Botta, Maurizio