Identification of small molecules uncoupling the Notch::Jagged interaction through an integrated high-throughput screening.
Identification of small molecules uncoupling the Notch::Jagged interaction through an integrated high-throughput screening.
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DOI：
10.1371/journal.pone.0182640
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Chiaramonte R
中科院分区：
文献类型：
--
作者：
Platonova N;Parravicini C;Sensi C;Paoli A;Colombo M;Neri A;Eberini I;Chiaramonte R
Notch信号传导在包括生长、分化、细胞命运决定和干性的若干细胞功能中起重要作用。Notch活性的增加与几种类型的癌症有关。Notch信号传导的激活由Notch受体（Notch 1 -4）与在相邻细胞上表达的5种不同配体（Jagged 1 -2和Dll 1 -3-4）的相互作用触发。目前，抑制Notch信号传导的间接方法是基于抑制由γ-分泌酶催化的Notch活化的关键步骤，从而影响几种不同的γ-分泌酶底物;相反，直接策略获得基于抗体的药物的优势。Jagged介导的Notch激活在癌细胞生物学中起着关键作用的证据以及与周围微环境的相互作用促使我们开发了一种策略，通过使用基于小分子的前所未有的方法解偶联Notch与Jagged的相互作用来直接抑制Notch激活。我们建立了一个筛选策略的基础上：蛋白质：：蛋白质对接的晶体结构的刻缺蛋白1与锯齿状蛋白1;比较建模的刻缺蛋白2：锯齿状蛋白2复合物，基于刻缺蛋白1：：锯齿状蛋白1复合物;在电脑高通量筛选针对刻缺蛋白2相互作用表面的虚拟化学文库含有大量的各种分子市售。所选化合物的预测药理活性通过基因报告和活力测定在体外进行验证。该方法导致成功鉴定具有不同抗增殖效力和功效的两种候选物。这代表了合理鉴定候选分子的第一步，用于开发完全新颖的药物，以抑制癌症中的Notch信号传导。
Notch signaling plays an important role in several cellular functions including growth, differentiation, cell fate determination and stemness. Increased Notch activity has been linked to several types of cancers. Activation of Notch signaling is triggered by the interaction of Notch receptors (Notch1-4) with 5 different ligands (Jagged1-2 and Dll1-3-4) expressed on the neighbouring cells. Currently, indirect approaches to inhibit Notch signalling are based on the inhibition of the key step of Notch activation catalyzed by the γ-Secretase and thereby affect several different γ-Secretase substrates; conversely direct strategies get advantage of antibody-based drugs. The evidence that Jagged-mediated Notch activation plays a key role in cancer cell biology and the interplay with the surrounding microenvironment prompted us to develop a strategy to directly inhibit Notch activation by uncoupling its interaction with the Jagged, using an unprecedented approach based on small molecules. We set-up a screening strategy based on: protein::protein docking of crystallographic structures of Notch1 with Jagged1; comparative modelling of the Notch2:Jagged2 complex, based on the Notch1::Jagged1 complex; in silico high-throughput screening directed to Notch2 interaction surface of a virtual chemical library containing a large variety of molecules commercially available. The predicted pharmacological activity of the selected compounds was validated in vitro by a gene reporter and a viability assay. This approach led to the successful identification of two candidates with different anti-proliferative potency and efficacy. This represents the first step towards the rational identification of candidate molecules for the development of entirely novel drugs directed to inhibit Notch signaling in cancer.
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DOI：
10.1016/j.bbrc.2012.06.065
发表时间：
2012-07-20
影响因子：
3.1
作者：
Lee SH;Hong HS;Liu ZX;Kim RH;Kang MK;Park NH;Shin KH
通讯作者：
Shin KH
影响因子：
11.2
作者：
Hu W;Liu T;Ivan C;Sun Y;Huang J;Mangala LS;Miyake T;Dalton HJ;Pradeep S;Rupaimoole R;Previs RA;Han HD;Bottsford-Miller J;Zand B;Kang Y;Pecot CV;Nick AM;Wu SY;Lee JS;Sehgal V;Ram P;Liu J;Tucker SL;Lopez-Berestein G;Baggerly KA;Coleman RL;Sood AK
通讯作者：
Sood AK
影响因子：
--
作者：
Colombo M;Galletti S;Garavelli S;Platonova N;Paoli A;Basile A;Taiana E;Neri A;Chiaramonte R
通讯作者：
Chiaramonte R
影响因子：
--
作者：
Colombo M;Thümmler K;Mirandola L;Garavelli S;Todoerti K;Apicella L;Lazzari E;Lancellotti M;Platonova N;Akbar M;Chiriva-Internati M;Soutar R;Neri A;Goodyear CS;Chiaramonte R
通讯作者：
Chiaramonte R
影响因子：
2.9
作者：
Labute, Paul
通讯作者：
Labute, Paul