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Molecular Modeling of ALK L1198F and/or G1202R Mutations to Determine Differential Crizotinib Sensitivity

Yu-Chung Chuang1, Bo-Yen Huang1, Hsin-Wen Chang1

  • 1Department of Life Sciences, National University of Kaohsiung, Kaohsiung, Taiwan.

Scientific Reports
|August 8, 2019
PubMed

Insights

Anaplastic lymphoma kinase (ALK) mutations affect crizotinib response in non-small cell lung cancer. Molecular modeling reveals G1202R mutation hinders drug binding, while L1198F enhances it, guiding future kinase inhibitor development.

Area of Science:

  • Molecular biology
  • Pharmacology
  • Computational chemistry

Background:

  • Anaplastic lymphoma kinase (ALK) is a key therapeutic target in non-small cell lung cancer (NSCLC).
  • Crizotinib, a type I kinase inhibitor, targets the ATP binding site of ALK.
  • Specific ALK mutations, such as G1202R and L1198F, influence crizotinib sensitivity.

Purpose of the Study:

  • To elucidate the molecular mechanisms behind varied crizotinib sensitivities in ALK mutants.
  • To investigate the impact of G1202R and L1198F mutations on crizotinib binding.
  • To provide insights for developing improved kinase inhibitors for NSCLC treatment.

Main Methods:

  • Conducted molecular modeling simulations.
  • Analyzed the structural interactions between crizotinib and wild-type/mutant ALK proteins.
  • Correlated structural findings with experimental drug response data (IC50 values).

Main Results:

  • The ALK G1202R mutation causes steric hindrance, reducing crizotinib accessibility and efficacy.
  • The ALK L1198F mutation enlarges the binding pocket entrance and enhances crizotinib sensitivity through hydrophobic interactions.
  • The double mutant L1198F/G1202R shows alleviated steric hindrance, maintaining similar response to wild-type ALK.

Conclusions:

  • Mutated residues near the ATP pocket significantly tune crizotinib response in ALK.
  • Understanding these structural-functional relationships can guide the design of next-generation ALK inhibitors.
  • Findings are relevant for overcoming crizotinib resistance in NSCLC, similar to resistance mechanisms in ROS1 and MET.

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