Design, synthesis and biological evaluation of novel indolin-2-one derivatives as potent second-generation TRKs
Qiaohua Qin1, Qinglin Fu1, Xin Wang1
1Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang, 110016, PR China.
Abstract:
Tropomyosin receptor kinases (TRKs) are effective targets for anti-cancer drug discovery. The first-generation type I TRKs inhibitors, larotrectinib and entrectinib, exhibit durable disease control in the clinic. The emergence of acquired resistance mediated by secondary mutations in the TRKs domain significantly reduces the therapeutic efficacy of these two drugs, indicating an unmet clinical need. In this study, we designed a potent and orally bioavailable TRK inhibitor, compound 24b, using a molecular hybridization strategy. Compound 24b exhibited significant inhibitory potency against multiple TRK mutants in both biochemical and cellular assays. Furthermore, compound 24b induced apoptosis of Ba/F3-TRKAG595R and Ba/F3-TRKAG667C cells in a dose-dependent manner. Additionally, compound 24b exhibited moderate kinase selectivity. In vitro stability revealed that compound 24b showed excellent plasma stability (t1/2 > 289.1 min) and moderate liver microsomal stability (t1/2 = 44.3 min). Pharmacokinetic studies have revealed that compound 24b is an orally bioavailable TRK inhibitor with a good oral bioavailability of 116.07%. These results indicate that compound 24b be used as a lead molecule for further modifications to overcome drug-resistant mutants of TRK.
Insights
A new TRK inhibitor, compound 24b, effectively targets TRK mutations that cause resistance to current therapies. This orally bioavailable drug shows promise for overcoming acquired resistance in cancer treatment.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Tropomyosin receptor kinases (TRKs) are key targets in anti-cancer drug discovery.
- First-generation TRK inhibitors like larotrectinib and entrectinib show clinical efficacy but face acquired resistance due to TRK mutations.
- There is a critical need for novel TRK inhibitors effective against resistant mutants.
Purpose of the Study:
- To design and characterize a novel, potent, and orally bioavailable TRK inhibitor.
- To evaluate the efficacy of the new inhibitor against TRK mutations conferring resistance.
- To assess the in vitro stability and pharmacokinetic properties of the novel inhibitor.
Main Methods:
- Molecular hybridization strategy was employed to design compound 24b.
- Biochemical and cellular assays were used to determine inhibitory potency against TRK and its mutants.
- In vitro stability (plasma and liver microsomes) and pharmacokinetic studies (oral bioavailability) were conducted.
- Apoptosis induction in TRK-mutant cell lines was assessed.
Main Results:
- Compound 24b demonstrated significant inhibitory potency against multiple TRK mutants.
- It effectively induced apoptosis in Ba/F3-TRKAG595R and Ba/F3-TRKAG667C cells.
- Compound 24b exhibited excellent plasma stability and moderate liver microsomal stability.
- Pharmacokinetic studies confirmed good oral bioavailability (116.07%).
Conclusions:
- Compound 24b is a potent, orally bioavailable TRK inhibitor effective against resistant TRK mutants.
- It possesses favorable in vitro stability and pharmacokinetic profiles.
- Compound 24b serves as a promising lead molecule for developing next-generation TRK-targeted cancer therapies.
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