Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations Article Swipe

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Zuqin Wang , Jie Wang , Yongjin Wang , Shuang Xiang , Hengliang Zhou , Shukai Song , Xiaojuan Song , Zhengchao Tu , Yang Zhou , Ke Ding , Zhimin Zhang , Zhang Zhang , Xiaoyun Lu ·

YOU? · · 2023 · Open Access · · DOI: https://doi.org/10.1021/acs.jmedchem.3c00899

The solvent-front (SF), gatekeeper, and xDFG motif mutations of tropomyosin receptor kinase (TRK) mediating acquired resistance of larotrectinib and entrectinib represent an unmet clinical need. To date, no effective drugs are being approved to overcome these mutants. Thus, a series of macrocycle compounds were designed and synthesized as new type II TRK inhibitors to combat clinically relevant mutations. The representative compound 10g exhibited excellent potency against wide type TRKA/C, TRKA^G595R, TRKA^G667C_, and TRKA^F589L with IC₅₀ values of 5.21, 4.51, 6.77, 1.42, and 6.13 nM, respectively, and a good kinome selectivity against 378 kinases. 10g also strongly suppressed the proliferation of Ba/F3 cells transfected with SF, GK, xDFG, and others (Val to Met) single mutants with IC₅₀ values of 1.43-47.56 nM. Moreover, 10g demonstrated ideal antitumor efficacy in both BaF3-CD74-NTRK1^G595R and BaF3-CD74-NTRK1^G667C xenograft models. The study provides a promising lead compound for pan-anticancer drug discovery.

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Trk receptor Chemistry Tropomyosin receptor kinase A Kinase Drug discovery Pharmacology Stereochemistry Receptor Biochemistry Neurotrophin Medicine

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Type: article
Language: en
Landing Page: https://doi.org/10.1021/acs.jmedchem.3c00899
OA Status: green
Cited By: 11
References: 28
Related Works: 10
OpenAlex ID: https://openalex.org/W4386499014

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DOI: https://doi.org/10.1021/acs.jmedchem.3c00899

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Title: Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations

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Language: en

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Publication year: 2023

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Publication date: 2023-09-07

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Authors: Zuqin Wang, Jie Wang, Yongjin Wang, Shuang Xiang, Hengliang Zhou, Shukai Song, Xiaojuan Song, Zhengchao Tu, Yang Zhou, Ke Ding, Zhimin Zhang, Zhang Zhang, Xiaoyun Lu

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Landing page: https://doi.org/10.1021/acs.jmedchem.3c00899

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OA URL: https://doi.org/10.7270/q20p14gt

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Concepts: Trk receptor, Chemistry, Tropomyosin receptor kinase A, Kinase, Drug discovery, Pharmacology, Stereochemistry, Receptor, Biochemistry, Neurotrophin, Medicine

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Cited by: 11

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