Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor.
J Med Chem
; 59(19): 9080-9093, 2016 10 13.
Article
en En
| MEDLINE
| ID: mdl-27564586
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 and ADME-PK properties that are suitable for further evaluation. The reversible, noncovalent inhibitors described complement the covalent pan-mutant EGFR inhibitors that have shown encouraging results in recent clinical trials.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Carcinoma de Pulmón de Células no Pequeñas
/
Inhibidores de Proteínas Quinasas
/
Receptores ErbB
/
Neoplasias Pulmonares
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2016
Tipo del documento:
Article
Pais de publicación:
Estados Unidos