Sign in to use this feature.

Years

Between: -

Subjects

remove_circle_outline
remove_circle_outline

Journals

Article Types

Countries / Regions

Search Results (1)

Search Parameters:
Keywords = xDFG mutation

Order results
Result details
Results per page
Select all
Export citation of selected articles as:
16 pages, 3144 KB  
Article
JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo
by Jie Wang, Yang Zhou, Xia Tang, Xiuwen Yu, Yongjin Wang, Shingpan Chan, Xiaojuan Song, Zhengchao Tu, Zhimin Zhang, Xiaoyun Lu, Zhang Zhang and Ke Ding
Molecules 2022, 27(19), 6500; https://doi.org/10.3390/molecules27196500 - 1 Oct 2022
Cited by 3 | Viewed by 3883
Abstract
The tropomyosin receptor kinases (TRKs) have been validated as effective targets in anticancer drug discovery. Two first-generation TRK inhibitors have been approved into market and displayed an encouraging therapeutic response in cancer patients harboring TRK fusion proteins. However, acquired resistance mediated by secondary [...] Read more.
The tropomyosin receptor kinases (TRKs) have been validated as effective targets in anticancer drug discovery. Two first-generation TRK inhibitors have been approved into market and displayed an encouraging therapeutic response in cancer patients harboring TRK fusion proteins. However, acquired resistance mediated by secondary TRK mutations especially in the xDFG motif remains an unsolved challenge in the clinic. Herein, we report the preclinical pharmacological results of JND4135, a new type II pan-TRK inhibitor, in overcoming TRK mutant resistance, including the xDFG mutations in vitro and in vivo. At a low nanomolar level, JND4135 displays a strong activity against wild-type TRKA/B/C and secondary mutations involving xDFG motif substitutions in kinase assays and cellular models; occupies the TRK proteins for an extended time; and has a slower dissociation rate than other TRK inhibitors. Moreover, by intraperitoneal injection, JND4135 exhibits tumor growth inhibition (TGI) of 81.0% at a dose of 40 mg/kg in BaF3-CD74-TRKA-G667C mice xenograft model. Therefore, JND4135 can be considered as a lead compound for drug discovery overcoming the resistance of TRK inhibitor drugs mediated by xDFG mutations. Full article
Show Figures

Figure 1

Back to TopTop