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Updated: Jun 25, 2025
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Discovery of potent CSK inhibitors through integrated virtual screening and molecular dynamic simulation
Roufen Chen1,2, Yuchen Wang2, Zheyuan Shen2
1Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou, China.
Abstract:
Oncogenic overexpression or activation of C-terminal Src kinase (CSK) has been shown to play an important role in triple-negative breast cancer (TNBC) progression, including tumor initiation, growth, metastasis, drug resistance. This revelation has pivoted the focus toward CSK as a potential target for novel treatments. However, until now, there are few inhibitors designed to target the CSK protein. Responding to this, our research has implemented a comprehensive virtual screening protocol. By integrating energy-based screening methods with AI-driven scoring functions, such as Attentive FP, and employing rigorous rescoring methods like Glide docking and molecular mechanics generalized Born surface area (MM/GBSA), we have systematically sought out inhibitors of CSK. This approach led to the discovery of a compound with a potent CSK inhibitory activity, reflected by an IC50 value of 1.6 nM under a homogeneous time-resolved fluorescence (HTRF) bioassay. Subsequently, molecule 2 exhibits strong growth inhibition of MD anderson - metastatic breast (MDA-MB) -231, Hs578T, and SUM159 cells, showing a level of growth inhibition comparable to that observed with dasatinib. Treatment with molecule 2 also induced significant G1 phase accumulation and cell apoptosis. Furthermore, we have explored the explicit binding interactions of the compound with CSK using molecular dynamics simulations, providing valuable insights into its mechanism of action.
Insights
Researchers identified a novel compound that potently inhibits C-terminal Src kinase (CSK), a key driver in triple-negative breast cancer (TNBC). This discovery offers a promising new therapeutic avenue for TNBC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- C-terminal Src kinase (CSK) overexpression/activation is implicated in triple-negative breast cancer (TNBC) progression, driving tumor initiation, growth, metastasis, and drug resistance.
- Targeting CSK presents a promising strategy for novel TNBC therapeutics, yet effective inhibitors are scarce.
Purpose of the Study:
- To identify and characterize novel inhibitors of C-terminal Src kinase (CSK) for potential triple-negative breast cancer (TNBC) therapy.
- To validate the efficacy and mechanism of action of a newly discovered CSK inhibitor.
Main Methods:
- Employed a comprehensive virtual screening protocol integrating energy-based methods, AI-driven scoring (Attentive FP), Glide docking, and MM/GBSA for rigorous rescoring.
- Utilized homogeneous time-resolved fluorescence (HTRF) bioassays to determine inhibitory activity (IC50).
- Assessed compound efficacy in inhibiting proliferation of TNBC cell lines (MDA-MB-231, Hs578T, SUM159) and analyzed cell cycle and apoptosis.
- Conducted molecular dynamics simulations to elucidate binding interactions between the compound and CSK.
Main Results:
- Discovered a potent CSK inhibitor with an IC50 of 1.6 nM.
- The identified molecule (molecule 2) demonstrated significant growth inhibition in multiple TNBC cell lines, comparable to dasatinib.
- Treatment with molecule 2 induced G1 phase cell cycle arrest and promoted apoptosis.
- Molecular dynamics simulations provided insights into the compound's binding interactions with CSK.
Conclusions:
- The novel CSK inhibitor exhibits potent anti-cancer activity against TNBC cells.
- This compound represents a promising lead for developing targeted therapies for triple-negative breast cancer.
- Further investigation into its mechanism and therapeutic potential is warranted.
Related Concept Videos
01:26Drug Discovery: Overview
02:34Inhibition of Cdk Activity