RESUMO
The clinical utility of approved EGFR small-molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system, a disease sanctuary site. Here, we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small-molecule EGFR kinase inhibitors that are selective for T790M-mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M-positive or -negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib). In addition, GNS-1486 showed superior potency against intracranial metastasis of EGFR-mutant lung adenocarcinoma. Our results offer a preclinical proof of concept for new EGFR kinase inhibitors with the potential to improve therapeutic index and efficacy against brain metastases in patients. Cancer Res; 77(5); 1200-11. ©2017 AACR.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Pulmonares/enzimologia , Neoplasias Pulmonares/patologia , Camundongos , Camundongos SCID , TransfecçãoRESUMO
An operationally convenient, one-pot, three-step sequence has been developed that provides access to 3-substituted 4-, 5-, 6-, and 7-azaindolines (2,3-dihydro-1H-pyrollopyridines) via intramolecular carbolithiation of the aryllithium derived from an appropriate (N,N-diallylamino)bromopyridine. Whereas cyclization proceeds as expected to give 1-allyl-3-methyl-4-azaindoline and 1-allyl-3-methyl-6-azaindoline following protonation of the 3-CH2Li group of the azaindoline, the isomeric 3-methyl-5-azaindoline and 3-methyl-7-azaindoline are generated as 3-methyl-N-allyl anions prior to quench with MeOH.
Assuntos
Compostos Aza/química , Indóis/química , Lítio/química , IsomerismoRESUMO
A mild, selective, and high-yielding method for oxidation of sulfides to sulfoxides using IBX and tetraethylammonium bromide in a variety of solvents is described. The method offers the advantage of short reaction times, no over-oxidation to sulfones, and compatibility to a wide range of functional groups.