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Ref Type Journal Article
PMID (30242093)
Authors Tanaka H, Sase H, Tsukaguchi T, Hasegawa M, Tanimura H, Yoshida M, Sakata K, Fujii T, Tachibana Y, Takanashi K, Higashida A, Hasegawa K, Ono Y, Oikawa N, Mio T
Title Selective TRK Inhibitor CH7057288 against TRK Fusion-Driven Cancer.
Journal Molecular cancer therapeutics
Vol 17
Issue 12
Date 2018 Dec
Abstract Text Members of the tropomyosin receptor kinase (TRK) family are expressed in their constitutively activated forms as a result of a gene fusion that occurs across a wide variety of cancer types. We have identified CH7057288 as a potent and selective TRK inhibitor that belongs to a novel chemical class. CH7057288 showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. Strong in vivo tumor growth inhibition was observed in subcutaneously implanted xenograft tumor models of TRK fusion-positive cells. Furthermore, in an intracranial implantation model mimicking brain metastasis, CH7057288 significantly induced tumor regression and improved event-free survival. Recently, resistant mutations in the kinase domain of TRK have been reported in patients who show disease progression after treatment with the TRK inhibitors now under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against one of these resistant mutants as it did to wild-type TRK. An X-ray crystal structure of the TRKA and CH7057288 complex supported the activity against the mutant. In addition, gene expression analysis revealed that CH7057288 suppressed MAPK and E2F pathways as downstream signaling of TRK fusion. Therefore, CH7057288 could be a promising therapeutic agent for TRK fusion-positive cancer.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
CH7057288 CH7057288 1 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
CH7057288 Trk Receptor Inhibitor (Pan) 23 CH7057288 selectivity inhibits NTRK1, 2, and 3, resulting in decreased downstream signaling and potentially resulting in reduced growth of tumors harboring NTRK fusions (PMID: 30242093).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ETV6 - NTRK3 acute myeloid leukemia sensitive CH7057288 Preclinical - Cell line xenograft Actionable In a preclinical study, CH7057288 inhibited NTRK phosphorylation and downstream signaling and reduced growth of acute myeloid leukemia cells harboring ETV6-NTRK3 in culture, and induced tumor regression in xenograft models (PMID: 30242093). 30242093