1. Academic Validation
  2. Discovery of First-In-Class Potent and Selective Tropomyosin Receptor Kinase Degraders

Discovery of First-In-Class Potent and Selective Tropomyosin Receptor Kinase Degraders

  • J Med Chem. 2020 Dec 10;63(23):14562-14575. doi: 10.1021/acs.jmedchem.0c01342.
Liqun Chen 1 Yanke Chen 1 Chunyan Zhang 1 Bingyang Jiao 1 Sheng Liang 1 Qiong Tan 1 Hongyu Chai 1 Weihua Yu 1 Yongzheng Qian 1 Hui Yang 1 Wuyi Yao 1 Jianguo Yu 1 Ying Luo 2 Michael Plewe 2 Jialiang Wang 2 1 Xiao-Ran Han 2 1 Jing Liu 2
Affiliations

Affiliations

  • 1 Cullgen (Shanghai), Inc., 230 ChuanHong Road, Building 6, Chuansha, Pudong New Area, Shanghai 201202, People's Republic of China.
  • 2 Cullgen Inc., 12671 High Bluff Drive Suite 130, San Diego, California 92130, United States.
Abstract

We report compounds 5 (CG416) and 6 (CG428) as two first-in-class tropomyosin receptor kinase (Trk) degraders that target the intracellular kinase domain of Trk. Degraders 5 and 6 reduced levels of the tropomyosin 3 (TPM3)-TRKA fusion protein in KM12 colorectal carcinoma cells and inhibited downstream PLCγ1 signaling at sub-nanomolar concentrations. Both degraders also degraded human wild-type TrkA with similar potency. Interestingly, both degraders, especially 6, showed selectivity for the degradation of endogenous TPM3-TRKA over ectopically expressed ATP/GTP binding protein-like 4 (AGBL4)-TRKB or ETS variant transcription factor 6 (ETV6)-TRKC fusion proteins in KM12 cells. Global proteomic profiling assays demonstrated that 5 is highly selective for the intended target. TPM3-TRKA protein degradation induced by 5 and 6 was further confirmed to be mediated through Cereblon and the ubiquitin-proteasome system. Compared with the parental Trk kinase inhibitor, both degraders exhibited higher potency for inhibiting growth of KM12 cells. Moreover, both 5 and 6 showed good plasma exposure levels in mice. Therefore, 5 and 6 are valuable chemical tool compounds for investigating the in vivo function of Trk fusion during tumorigenesis. Our study also paves the way for pharmacological degradation of Trk.

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