Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy

Shuang Xiang; Jie Wang; Huisi Huang; Zuqin Wang; Xiaojuan Song; Yang Zhou; Feng Jin; Xun He; Zhi-Min Zhang; Zhengchao Tu; Ke Ding; Zhang Zhang; Xiaoyun Lu

doi:10.1016/j.ejmech.2022.114899

Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy

Eur J Med Chem. 2023 Jan 5;245(Pt 1):114899. doi: 10.1016/j.ejmech.2022.114899. Epub 2022 Nov 12.

Authors

Shuang Xiang¹, Jie Wang¹, Huisi Huang¹, Zuqin Wang¹, Xiaojuan Song¹, Yang Zhou¹, Feng Jin², Xun He², Zhi-Min Zhang¹, Zhengchao Tu¹, Ke Ding¹, Zhang Zhang³, Xiaoyun Lu⁴

Affiliations

¹ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou, 510632, China.
² Shenzhen NewDEL Biotech Co., Ltd., Guanguang RD, Longhua Dis, Shenzhen, 518110, China.
³ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou, 510632, China. Electronic address: zhang_zhang@jnu.edu.cn.
⁴ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou, 510632, China. Electronic address: luxy2016@jnu.edu.cn.

PMID: 36410169
DOI: 10.1016/j.ejmech.2022.114899

Abstract

TRK xDFG mutation-induced acquired resistance of 1^st generation inhibitors larotrectinib and entrectinib remains an unmet clinical need. Here we report a series of 6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-based derivatives as selective type II TRK inhibitors by hybridization. A representative compound 12d potently inhibited TRKA/B/C and TRKA^G667C with IC₅₀ values of 3.3, 6.4, 4.3 and 9.4 nM, respectively. 12d potently suppressed proliferation of a panel of Ba/F3 cells stably transformed with wild type, xDFG as well as solvent-front (SF) mutant TRK fusion proteins. Compared with larotrectinib and selitrectinib, 12d displayed superior inhibitory activity towards Ba/F3 cells harboring CD74-TRKA^G667C and ETV6-TRKC^G696C with IC₅₀ values of 2.6 and 6.1 nM, respectively. Moreover, 12d also exhibited potent antiproliferation activity against Ba/F3-ETV6-TRKC^G623R and Ba/F3-ETV6-TRKC^G623E mutants with IC₅₀ values of 31.0 and 28.2 nM, respectively. This work provided a new potential type II TRK inhibitor-based lead compound for the treatment of TRK driven cancers.

Keywords: Clinical resistance; Hybridization; TRKs; Type II; xDFG mutation.

MeSH terms

Humans
Mutation
Neoplasms* / drug therapy
Neoplasms* / genetics
Protein Kinase Inhibitors* / pharmacology

Substances

Protein Kinase Inhibitors