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

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Chen L,Chen Y,Zhang C,Jiao B,Liang S,Tan Q,Chai H,Yu W,Qian Y,Yang H,Yao W,Yu J,Luo Y,Plewe M,Wang J,Han XR,Liu J

doi

10.1021/acs.jmedchem.0c01342

subject

Has Abstract

pub_date

2020-12-10 00:00:00

pages

14562-14575

issue

23

eissn

0022-2623

issn

1520-4804

journal_volume

63

pub_type

杂志文章

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