Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy.
Eur J Med Chem
; 245(Pt 1): 114899, 2023 Jan 05.
Article
em En
| MEDLINE
| ID: mdl-36410169
ABSTRACT
TRK xDFG mutation-induced acquired resistance of 1st generation inhibitors larotrectinib and entrectinib remains an unmet clinical need. Here we report a series of 6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-based derivatives as selective type II TRK inhibitors by hybridization. A representative compound 12d potently inhibited TRKA/B/C and TRKAG667C with IC50 values of 3.3, 6.4, 4.3 and 9.4 nM, respectively. 12d potently suppressed proliferation of a panel of Ba/F3 cells stably transformed with wild type, xDFG as well as solvent-front (SF) mutant TRK fusion proteins. Compared with larotrectinib and selitrectinib, 12d displayed superior inhibitory activity towards Ba/F3 cells harboring CD74-TRKAG667C and ETV6-TRKCG696C with IC50 values of 2.6 and 6.1 nM, respectively. Moreover, 12d also exhibited potent antiproliferation activity against Ba/F3-ETV6-TRKCG623R and Ba/F3-ETV6-TRKCG623E mutants with IC50 values of 31.0 and 28.2 nM, respectively. This work provided a new potential type II TRK inhibitor-based lead compound for the treatment of TRK driven cancers.
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MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
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Neoplasias
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article