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

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

Publication History

Received: 21 January 2025

Accepted after revision: 05 March 2025

Accepted Manuscript online:
05 March 2025

Article published online:
15 April 2025

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