2. Academic Validation
  3. JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo

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

  • Molecules. 2022 Oct 1;27(19):6500. doi: 10.3390/molecules27196500.
Jie Wang 1,  Yang Zhou 1,  Xia Tang 1,  Xiuwen Yu 1,  Yongjin Wang 1,  Shingpan Chan 1,  Xiaojuan Song 2,  Zhengchao Tu 2,  Zhimin Zhang 1,  Xiaoyun Lu 1,  Zhang Zhang 1,  Ke Ding 1 3
Affiliations

Affiliations

  • 1 International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development, Ministry of Education (MoE) of People's Republic of China, College of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China.
  • 2 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Guangzhou Science Park, Guangzhou 510530, China.
  • 3 State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Road, Shanghai 200032, China.
PMID: 36235036 DOI: 10.3390/molecules27196500
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.

Keywords

JND4135; TRK; resistance; xDFG mutation.

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