JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo

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 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.

Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

“…10 ). However, the poor pharmacokinetic properties of 16 hinders its further development 95 , 101 . In order to exploit novel selective TRK inhibitors, scaffold hopping strategy was employed to obtain a series of imidazo[1,2- b ]pyridazine derivatives based on 16 .…”

Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations

“…Even so, these type II inhibitors were resistant to SF mutations. Recently, several new type II TRK inhibitors that can effectively overcome xDFG mutations have been reported (Figure S1), some of which show an anticancer effect in different NTRK gene fusion-driven Ba/F3 cells or KM12 tumor cells inoculated allograft or xenograft mouse models in vivo. − However, these inhibitors are still in early biological studies. Thus, novel selective TRK inhibitors that can efficiently inhibit SF, xDFG, and GK mutations are urgently needed.…”