Synlett
DOI: 10.1055/a-2551-5752
letter
Small Molecules in Medicinal Chemistry

Development of a Novel Tropomyosin Receptor Kinase Inhibitor Based on Structure–Activity Relationships: Identification of a Promising Clinical Candidate

Toshiya Ito  ∗
,
Kazutomo Kinoshita
,
Masaki Tomizawa
,
Shojiro Shinohara
,
Hiroki Nishii
,
Hiroshi Tanaka
,
Shino Kuramoto
,
Nobuhiro Oikawa
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Abstract

Tropomyosin receptor kinase (TRK) inhibitors have emerged as promising therapeutic agents for various cancers. In this study, we report the discovery and characterization of CH7070868, a novel and potent TRK-selective inhibitor. Through structure–activity relationship studies, we optimized the lead compound (CH7057288) to achieve superior TRK inhibition while reducing the risk of drug–drug interactions (CYP3A4 induction). CH7070868 demonstrated high selectivity for TRK over other kinases (KDR and LCK) and exhibited potent inhibitory activity in both biochemical and cellular assays. Our findings suggest that CH7070868 represents a promising candidate for further development as a next-generation TRK inhibitor with an enhanced efficacy.

Key words

TRK inhibitor - structure–activity relationship - CH7070868 - NTRK fusion gene - antiproliferative activity - CYP3A4 induction - selectivity - hydroxy group

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2551-5752.
  • Supporting Information


Publication History

Received: 21 January 2025

Accepted after revision: 05 March 2025

Accepted Manuscript online:
05 March 2025

Article published online:
15 April 2025

© 2025. Thieme. All rights reserved

Georg Thieme Verlag KG
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