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

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

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Neurotrophic receptor kinase(NTRK)fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors,and tropomyosin receptor kinase(TRK)has been considered as an attractive therapeutic target for"pan-cancer"harboring these fusions.Currently,two generations TRK in-hibitors have been developed.The representative second-generation inhibitors selitrectinib and repotrec-tinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target mutations.However,xDFG(TRKAG667C/A/S,homologous TRKCG696C/A/S)and some double mutations still confer resistance to seli-trectinib and repotrectinib,and overcoming these resistances represents a major unmet clinical need.In this review,we summarize the acquired resistance mechanism of the first-and second-generation TRK inhibitors,and firstly put forward the emerging selective type Ⅱ TRK inhibitors to overcome xDFG mu-tations mediated resistance.Additionally,we concluded our perspectives on new challenges and future directions in this field.

NTRK fusionsTRK kinaseClinical resistancexDFG mutationsSelective type Ⅱ inhibitors

Shuang Xiang、Xiaoyun Lu

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International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education(MOE),Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,Guangzhou City Key Laboratory of Precision Chemical Drug Development,School of Pharmacy,Jinan University,Guangzhou 510632,China

National Natural Science Foundation of ChinaNatural Science Foundation of Guangdong Province,ChinaOpening Project of State Key Laboratory of Respiratory Disease,ChinaOpening Project of Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,ChinaWang Kuancheng Young Scholar of Jinan University

822737632022A-1515011939SKLRD-OP-2023132020B1212060034

2024

10.1016/j.apsb.2023.11.010

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(2)
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