A drug discovery platform to identify compounds that inhibit EGFR triple mutants.
A drug discovery platform to identify compounds that inhibit EGFR triple mutants.
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DOI：
10.1038/s41589-020-0484-2
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发表时间：
2020-05
影响因子：
14.8
通讯作者：
Stagljar I
中科院分区：
文献类型：
--
作者：
Saraon P;Snider J;Kalaidzidis Y;Wybenga-Groot LE;Weiss K;Rai A;Radulovich N;Drecun L;Vučković N;Vučetić A;Wong V;Thériault B;Pham NA;Park JH;Datti A;Wang J;Pathmanathan S;Aboualizadeh F;Lyakisheva A;Yao Z;Wang Y;Joseph B;Aman A;Moran MF;Prakesch M;Poda G;Marcellus R;Uehling D;Samaržija M;Jakopović M;Tsao MS;Shepherd FA;Sacher A;Leighl N;Akhmanova A;Al-Awar R;Zerial M;Stagljar I
受体酪氨酸激酶(RTK)是一种跨膜受体，因其在疾病中的作用而具有重要的临床意义。从历史上看，靶向RTKs的治疗药物是通过体外激酶分析来确定的。然而，由于耐药性的频繁发展，需要寻找更多种类的化合物来抑制突变的RTK，而不是野生型RTK。在这里，我们描述了MaMTH-DS(哺乳动物膜双杂交药物筛选)，这是一个高通量鉴定针对RTK功能蛋白-蛋白质相互作用的小分子的活细胞平台。我们将MaMTH-DS应用于对最新一代临床批准的酪氨酸激酶抑制剂(TKIs)具有抗药性的致癌表皮生长因子受体(EGFR)突变。我们鉴定了四种突变特异性化合物，其中两种是传统的体外激酶分析无法检测到的。其中一个靶点通过一种新的作用机制突变EGFR，不同于经典的TKI抑制。我们的结果表明，MaMTH-DS是对传统药物筛选方法的有力补充。
Receptor Tyrosine Kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (Mammalian Membrane Two-Hybrid Drug Screening), a live-cell platform for high-throughput identification of small-molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic Epidermal Growth Factor Receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a novel mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.
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影响因子：
3
作者：
Sausville, Edward;LoRusso, Patricia;Carducci, Michael;Carter, Judith;Quinn, Mary F.;Malburg, Lisa;Azad, Nilofer;Cosgrove, David;Knight, Richard;Barker, Peter;Zabludoff, Sonya;Agbo, Felix;Oakes, Patricia;Senderowicz, Adrian
通讯作者：
Senderowicz, Adrian
DOI：
10.1016/s1470-2045(18)30240-7
发表时间：
2018-07
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Cortes J;Perl AE;Döhner H;Kantarjian H;Martinelli G;Kovacsovics T;Rousselot P;Steffen B;Dombret H;Estey E;Strickland S;Altman JK;Baldus CD;Burnett A;Krämer A;Russell N;Shah NP;Smith CC;Wang ES;Ifrah N;Gammon G;Trone D;Lazzaretto D;Levis M
通讯作者：
Levis M
影响因子：
48
作者：
Gibson, Daniel G.;Young, Lei;Smith, Hamilton O.
通讯作者：
Smith, Hamilton O.
影响因子：
7.2
作者：
Mellman, Ira;Yarden, Yosef
通讯作者：
Yarden, Yosef
影响因子：
--
作者：
Jia, Yong;Quinn, Christopher M;Talanian, Robert V
通讯作者：
Talanian, Robert V