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Optimization of Covalent Warhead Trajectory for KRASG12C Active-State Inhibition.

Matthew L Condakes1, Rita L Civiello1, Sirish Kaushik Lakkaraju2

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Researchers optimized KRAS G12C inhibitors by altering the covalent warhead trajectory. This angled approach enhanced potency and cellular activity without scaffold modification, offering a new design principle for active-state KRAS targeting.

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Area of Science:

  • Medicinal Chemistry
  • Structural Biology
  • Pharmacology

Background:

  • KRAS G12C mutations are key drivers in various cancers.
  • Developing selective inhibitors for KRAS G12C remains a therapeutic challenge.
  • Understanding inhibitor-target interactions is crucial for drug design.

Purpose of the Study:

  • To investigate the impact of covalent warhead trajectory on KRAS G12C inhibitor efficacy.
  • To identify novel trajectories that enhance potency and pharmacokinetic properties.
  • To establish a design principle for targeting the active state of KRAS.

Main Methods:

  • Structure-based drug design.
  • Computational modeling.
  • Biochemical and cellular assays.
  • Crystallography.

Main Results:

  • Novel covalent warhead trajectories were identified, enhancing compound potency without scaffold changes.
  • Unlike inactive-state inhibitors, active-state KRAS G12C inhibitors featured an angled warhead disposition.
  • Cocrystal structures revealed increased potency correlated with greater distance from the bound nucleotide.

Conclusions:

  • The trajectory of the covalent warhead is a critical determinant of active-state KRAS G12C inhibitor potency.
  • An angled warhead disposition represents a promising strategy for developing potent KRAS G12C inhibitors.
  • This study provides a generalizable design principle for targeting the active conformation of KRAS.