Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor
| Autor: | Charles Eigenbrot, Robert Heald, Bryan K. Chan, Michael D. Lainchbury, Timothy P. Heffron, Hans E. Purkey, Hank La, Philip Stephen Jackson, Stephen P. Schmidt, Gabriele Schaefer, Emily Chan, Marian C. Bryan, Ivana Yen, Jamie D. Knight, Daniel J. Burdick, Yuan Chen, Lily Shao, Richard L. Elliott, Jennafer Dotson, Shiva Malek, Christine Yu, Krista K. Bowman, Steve Sideris, Hanan Emily, Shumei Wang, Saundra Clausen, Siew Kuen Yeap, Eileen Mary Seward, Trisha Dela Vega |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Lung Neoplasms Mutant Antineoplastic Agents Crystallography X-Ray 03 medical and health sciences T790M Mice 0302 clinical medicine In vivo Carcinoma Non-Small-Cell Lung Cell Line Tumor Drug Discovery Animals Humans Epidermal growth factor receptor Binding site Lung Protein Kinase Inhibitors EGFR inhibitors Cell Proliferation biology Chemistry Point mutation Molecular biology In vitro respiratory tract diseases ErbB Receptors 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation biology.protein Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 59(19) |
| ISSN: | 1520-4804 |
| Popis: | Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR mutant positive non-small-cell lung cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against those first generation therapeutics. Herein, we describe the lead optimization of a series of reversible, pan-mutant (L858R, del746–750, T790M/L858R, and T790M/del746–750) EGFR inhibitors. By use of a noncovalent double mutant (T790M/L858R and T790M/del746–750) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del746–750) were introduced through a series of structure-guided modifications. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the single and double mutants of EGFR, demonstrating target engagement in vivo... |
| Databáze: | OpenAIRE |
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