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Ref Type Journal Article
PMID (36235036)
Authors Wang J, Zhou Y, Tang X, Yu X, Wang Y, Chan S, Song X, Tu Z, Zhang Z, Lu X, Zhang Z, Ding K
Title JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo.
Journal Vol Issue Date Pages Journal Short Title
Molecules (Basel, Switzerland) 27 19 2022 Oct 01 Molecules
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
JND4135 JND4135 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
JND4135 Trk Receptor Inhibitor (Pan) 31 JND4135 is a pan-NTRK inhibitor with activity against resistance mutations, which potentially leads to decreased tumor growth (PMID: 36235036).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NTRK1 G667C Advanced Solid Tumor predicted - sensitive JND4135 Preclinical - Biochemical Actionable In a preclinical study, JND4135 inhibited kinase activity of NTRK1 G667C in an in vitro assay (PMID: 36235036). 36235036