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A biophysical framework for double-drugging kinases.

C Kim1, H Ludewig1, A Hadzipasic1

  • 1Department of Biochemistry, Brandeis University and Howard Hughes Medical Institute, Waltham, MA 02454, USA.

Biorxiv : the Preprint Server for Biology
|March 30, 2023
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Summary
This summary is machine-generated.

Double-drugging kinases by targeting orthosteric and allosteric sites offers a synergistic approach to overcome drug resistance. This study quantifies cooperativity, revealing conformational shifts and reduced drug dosages for effective kinase inhibition.

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Area of Science:

  • Biochemistry and structural biology
  • Pharmacology and drug discovery

Background:

  • Kinase inhibition faces challenges from conserved active sites and resistance mutations.
  • Simultaneous targeting of orthosteric and allosteric sites ('double-drugging') shows promise for overcoming resistance.
  • Detailed biophysical characterization of cooperativity in kinase double-drugging is lacking.

Approach:

  • Developed a quantitative framework using isothermal titration calorimetry, FRET, coupled-enzyme assays, and X-ray crystallography.
  • Investigated cooperativity for Aurora A kinase (AurA) and Abelson kinase (Abl) with various modulator combinations.
  • Determined structural basis of cooperativity through X-ray crystal structures of double-drug complexes.

Key Points:

  • Identified both positive and negative cooperativity between orthosteric and allosteric modulators for AurA and Abl.
  • Demonstrated that conformational equilibrium shifts are central to the observed cooperativity.
  • Observed synergistic reduction in required drug dosages for achieving clinically relevant kinase inhibition levels.
  • Captured the first fully-closed conformation of Abl bound to positively cooperative modulators.

Conclusions:

  • Provides mechanistic and structural insights into kinase double-drugging strategies.
  • Highlights the potential for rational design of more effective kinase inhibitors.
  • Offers a framework for evaluating the cooperative effects of dual-site kinase inhibition.