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Lazertinib: breaking the mold of third-generation EGFR inhibitors
Kishan B Patel1, David E Heppner1,2,3
1Department of Chemistry, The State University of New York at Buffalo Natural Sciences Complex Buffalo NY 14260 USA davidhep@buffalo.edu.
Abstract:
Small molecules targeting activating mutations within the epidermal growth factor receptor (EGFR) are efficacious anticancer agents, particularly in non-small cell lung cancer (NSCLC). Among these, lazertinib, a third-generation tyrosine kinase inhibitor (TKI), has recently gained FDA approval for use in combination with amivantamab, a dual EGFR/MET-targeting monoclonal antibody. This review delves into the discovery and development of lazertinib underscoring the improvements in medicinal chemistry properties, especially in comparison with osimertinib. Analysis of its structure-activity relationships (SAR), as outlined in the patent literature, reveals the structural diversity explored enroute to the candidate molecule. The resulting structure of lazertinib is distinguished among other TKIs due to the combination of the hydrophobic phenyl and hydrophilic amine substituents on the pyrazole. The structural basis for the selectivity against the T790M mutation is enabled by the substituted pyrazole moiety, which facilitates both van der Waals and H-bonding interactions with the EGFR kinase domain. Insights from this case study offer lessons that can inform the future design of kinase inhibitors with improved safety and efficacy profiles for cancer treatment and other diseases.
Insights
Lazertinib, a third-generation EGFR inhibitor, shows improved medicinal chemistry properties and selectivity for cancer treatment. Its unique structure offers insights for designing future kinase inhibitors with enhanced safety and efficacy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Drug Discovery
Background:
- Activating mutations in epidermal growth factor receptor (EGFR) drive non-small cell lung cancer (NSCLC).
- Third-generation tyrosine kinase inhibitors (TKIs) like lazertinib target these mutations.
- Lazertinib is approved in combination with amivantamab for NSCLC treatment.
Purpose of the Study:
- To review the discovery and development of lazertinib.
- To compare lazertinib's medicinal chemistry properties with osimertinib.
- To elucidate the structure-activity relationships (SAR) and structural basis for lazertinib's selectivity.
Main Methods:
- Analysis of patent literature for SAR.
- Structural comparison of lazertinib with other TKIs.
- Examination of molecular interactions within the EGFR kinase domain.
Main Results:
- Lazertinib exhibits improved medicinal chemistry properties compared to osimertinib.
- Its unique pyrazole structure with hydrophobic and hydrophilic substituents confers selectivity.
- The pyrazole moiety facilitates van der Waals and H-bonding interactions, crucial for T790M mutation selectivity.
Conclusions:
- Lazertinib's development highlights advancements in TKI design.
- Its structural features provide a basis for improved kinase inhibitor development.
- This case study offers valuable insights for future cancer therapeutics and other disease treatments.
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