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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
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Structural pharmacological studies on EGFR T790M/C797S

Lu-Lu Kong1, Rui Ma1, Ming-Yu Yao2

  • 1Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.

Biochemical and Biophysical Research Communications
|May 1, 2017
PubMed

Insights

New reversible inhibitors are needed for EGFR-mutated lung cancers resistant to covalent drugs. Gö6976 shows promise by targeting resistant EGFR mutations, offering a potential new therapeutic strategy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Drug resistance in EGFR-mutated non-small cell lung cancer (NSCLC) is a significant clinical challenge.
  • Third-generation irreversible EGFR inhibitors are effective against T790M mutations but fail with the C797S resistance mutation.
  • Development of novel reversible inhibitors is crucial to overcome emerging resistance mechanisms.

Purpose of the Study:

  • To investigate the efficacy of Gö6976, a reversible inhibitor, against EGFR T790M and T790M/C797S mutations.
  • To elucidate the structural basis of Gö6976 binding to EGFR wild-type, T790M, and T790M/C797S mutants.
  • To provide insights for the development of next-generation EGFR inhibitors.

Main Methods:

  • Co-crystallization and structural determination of EGFR T790M/C797S + Gö6976 and T790M + Gö6976 complexes.
  • Enzyme kinetic assays for EGFR wild-type, T790M, and T790M/C797S.
  • Analysis of structural and functional data to understand drug-target interactions.

Main Results:

  • The C797S mutation minimally impacts EGFR kinase structure and function, but increases local hydrophilicity.
  • Complex crystal structures reveal the binding mode of Gö6976 to EGFR, explaining its preference for the T790M mutant.
  • Gö6976 demonstrates potential as a reversible inhibitor against EGFR resistance mutations.

Conclusions:

  • The C797S mutation does not abolish EGFR kinase activity but alters the binding site characteristics.
  • Gö6976's reversible binding mechanism offers an alternative to covalent inhibitors, bypassing C797S resistance.
  • Structural and kinetic data provide a foundation for designing improved EGFR-targeted therapies for resistant NSCLC.
Keywords:
C797SDrug-resistanceEGFRGö6976T790M

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