Design, synthesis, and Structure–Activity Relationships (SAR) of 3-vinylindazole derivatives as new selective tropomyosin receptor kinases (Trk) inhibitors

Structural Optimization and Structure–Activity Relationship Studies of 6,6-Dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one Derivatives as A New Class of Potent Inhibitors of Pan-Trk and Their Drug-Resistant Mutants

“…Point mutants occurred in the Trks kinase domains, which have been found to be the main causative factor leading to the drug resistance; typical point mutations include TrkA G595R , TrkA G667C , TrkA G667S , TrkA F589L , TrkC G623R , and TrkC G696A . − Discovery of new-generation Trks inhibitors that can conquer the drug resistance is a hot topic in recent years. Several compounds have already been reported to be able to overcome the drug resistance. − However, right now just two compounds [selitrectinib (LOXO195) and repotrectinib (TPX0005)] have entered clinical trials, and most of other Trks inhibitors have either low potency or poor kinase selectivity, limiting their moving forward. − Discovering more potent and selective new-generation Trks inhibitors is still an important and valuable work at present.…”

Discovery of Next-Generation Tropomyosin Receptor Kinase Inhibitors for Combating Multiple Resistance Associated with Protein Mutation

“…Ba/F3 cells expressing ETV6-TRKA WT , ETV6-TRKB WT , ETV6-TRKC WT , LMNA-TRKA G595R , LMNA-TRKA G667C , and LMNA-TRKA F589L were cultured in RPMI medium 1640 supplemented with 10% fetal bovine serum (FBS) at 37 °C in the air atmosphere containing 5% CO 2 . The cell proliferation inhibitory activities of Ba/F3 cell lines were determined according to the reported method. , Cells were seeded in 96-well plates (0.5 × 10 5 cells/well). Twenty-four hours later, compound 8 or 3 was added to the designated wells, and cells were incubated at 37 °C for additional 72 h. After the above treatment, CCK-8 was added into the 96-well plates (10 μL/well) and incubated with the cells for 3 h. OD450 and OD650 were determined by a microplate reader.…”

“…The cell proliferation inhibitory activities of Ba/F3 cell lines were determined according to the reported method. 37,38 Cells were seeded in 96-well plates (0.5 × 10 5 cells/well). Twenty-four hours later, compound 8 or 3 was added to the designated wells, and cells were incubated at 37 °C for additional 72 h. After the above treatment, CCK-8 was added into the 96-well plates (10 μL/well) and incubated with the cells for 3 h. OD450 and OD650 were determined by a microplate reader.…”

Discovery of Next-Generation Tropomyosin Receptor Kinase (TRK) Inhibitors for Combatting Resistance Associated with Protein Mutation

“…Ba/F3 cells expressing ETV6-TRKA WT , ETV6-TRKB WT , ETV6-TRKC WT , LMNA-TRKA G595R , LMNA-TRKA G667C , and LMNA-TRKA F589L were cultured in RPMI medium 1640 supplemented with 10% fetal bovine serum (FBS) at 37°C in the air containing 5% CO 2 atmosphere. The cell proliferation inhibitory activities of Ba/F3 cell lines were determined according to the reported method 42,43 . Cells were seeded in 96-well plates (0.5 × 10 5 cells/well).…”