Identification of small-molecule EGFR allosteric inhibitors by high-throughput docking

被引:17
作者
Caporuscio, Fabiana [1 ]
Tinivella, Annachiara [1 ]
Restelli, Valentina [2 ]
Semrau, Marta S. [3 ]
Pinzi, Luca [1 ]
Storici, Paola [3 ]
Broggini, Massimo [2 ]
Rastelli, Giulio [1 ]
机构
[1] Univ Modena & Reggio Emilia, Dept Life Sci, Via Campi 103, I-41125 Modena, Italy
[2] IRCCS, Ist Ric Farmacol Mario Negri, Via La Masa 19, I-20156 Milan, Italy
[3] Elettra Sincrotrone Trieste SCpA, SS 14 Km 163,5 AREA Sci Pk, I-34149 Trieste, Italy
关键词
allosteric inhibitors; EGFR; high-throughput docking; protein kinases; virtual screening; TYROSINE KINASE INHIBITORS; GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; PROTEIN-KINASES; RESISTANCE; DISCOVERY;
D O I
10.4155/fmc-2018-0063
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Aim: The EGFR inhibitors represent the first-line treatment of non-small-cell lung cancer. However, the emergence of resistance urgently requires the development of new inhibitors targeting drug-resistant mutants. Methodology: A recently released structure of an EGFR kinase domain in complex with an allosteric inhibitor and a mutant protein model derived from it were used to set up a low-cost high-throughput docking protocol for the fast identification of EGFR allosteric inhibitors. Conclusion: The virtual screening of commercially available compounds led to the identification of interesting new hit compounds. The most promising hit was confirmed to be a new allosteric inhibitor of wild-type and T790M/L858R double mutant EGFR which was able to inhibit the growth of non-small-cell lung cancer cell lines. [GRAPHICS] .
引用
收藏
页码:1545 / 1553
页数:9
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