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.
Shuang Xiang  1 ,  Jie Wang  1 ,  Huisi Huang  1 ,  Zuqin Wang  1 ,  Xiaojuan Song  1 ,  Yang Zhou  1 ,  Feng Jin  2 ,  Xun He  2 ,  Zhi-Min Zhang  1 ,  Zhengchao Tu  1 ,  Ke Ding  1 ,  Zhang Zhang  3 ,  Xiaoyun Lu  4
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: [email protected].
  • 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: [email protected].
PMID: 36410169 DOI: 10.1016/j.ejmech.2022.114899
Abstract

Trk xDFG mutation-induced acquired resistance of 1st 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 TrkAG667C 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-TRKAG667C and ETV6-TRKCG696C with IC50 values of 2.6 and 6.1 nM, respectively. Moreover, 12d also exhibited potent antiproliferation activity against Ba/F3-ETV6-TRKCG623R and Ba/F3-ETV6-TRKCG623E 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.
Products