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Application of MassSQUIRM for Quantitative Measurements of Lysine Demethylase Activity
Published on: March 11, 2012
Identification of osimertinib (AZD9291) as a lysine specific demethylase 1 inhibitor
Zhong-Rui Li1, Feng-Zhi Suo1, Bo Hu1
1School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, PR China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China; Key Laboratory of Technology of Drug Preparation, Ministry of Education of China, Zhengzhou 450001, PR China.
Abstract:
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In this study, osimertinib was characterized as a LSD1 inhibitor for the first time with an IC50 of 3.98 ± 0.3 μM and showed LSD1 inhibitory effect at cellular level. These findings provide new molecular skeleton for dual inhibitor for LSD1 and EGFR. Osimertinib could serve as a lead compound for further development for anti-NSCLC drug discovery with dual targeting.
Insights
Osimertinib, an EGFR inhibitor for non-small cell lung cancer (NSCLC), also inhibits LSD1. This discovery offers a new dual-targeting strategy for developing novel anti-NSCLC therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) approved for EGFR-mutated non-small cell lung cancer (NSCLC).
- Targeting specific mutations in NSCLC has improved patient outcomes.
Purpose of the Study:
- To investigate novel inhibitory activities of Osimertinib beyond its known EGFR inhibition.
- To characterize Osimertinib as a potential inhibitor of Lysine-Specific Demethylase 1 (LSD1).
Main Methods:
- Biochemical assays were performed to determine the IC50 of Osimertinib against LSD1.
- Cellular assays were conducted to confirm the LSD1 inhibitory effect of Osimertinib.
Main Results:
- Osimertinib demonstrated significant LSD1 inhibitory activity with an IC50 of 3.98 ± 0.3 μM.
- Osimertinib exhibited a measurable LSD1 inhibitory effect at the cellular level.
Conclusions:
- Osimertinib possesses dual inhibitory potential against both EGFR and LSD1.
- This finding presents a novel molecular scaffold for developing dual LSD1 and EGFR inhibitors for anti-NSCLC drug discovery.
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