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.

Identification of small-molecule EGFR allosteric inhibitors by high-Throughput docking / Caporuscio, Fabiana; Tinivella, Annachiara; Restelli, Valentina; Semrau, Marta S; Pinzi, Luca; Storici, Paola; Broggini, Massimo; Rastelli, Giulio. - In: FUTURE MEDICINAL CHEMISTRY. - ISSN 1756-8919. - 10:13(2018), pp. 1545-1553. [10.4155/fmc-2018-0063]

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

Caporuscio, Fabiana;Tinivella, Annachiara;Semrau, Marta S;Pinzi, Luca;Rastelli, Giulio
2018

Abstract

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.
16-mag-2018
10
13
1545
1553
Identification of small-molecule EGFR allosteric inhibitors by high-Throughput docking / Caporuscio, Fabiana; Tinivella, Annachiara; Restelli, Valentina; Semrau, Marta S; Pinzi, Luca; Storici, Paola; Broggini, Massimo; Rastelli, Giulio. - In: FUTURE MEDICINAL CHEMISTRY. - ISSN 1756-8919. - 10:13(2018), pp. 1545-1553. [10.4155/fmc-2018-0063]
Caporuscio, Fabiana; Tinivella, Annachiara; Restelli, Valentina; Semrau, Marta S; Pinzi, Luca; Storici, Paola; Broggini, Massimo; Rastelli, Giulio
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1172752
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