Structure-based drug repositioning explains ibrutinib as VEGFR2 inhibitor

Area of Science:

• Biochemistry
• Pharmacology
• Structural Biology

Background:

• Drug promiscuity allows binding to multiple targets, potentially causing side effects or enabling polypharmacology and drug repositioning.
• 3D structures of drug-target complexes facilitate studying drug promiscuity and predicting interactions.
• Dysregulated B-cells drive autoimmune diseases, making B-cell inactivating drugs a therapeutic target.

Purpose of the Study:

• To identify drugs that inactivate B-cells using structure-based drug repositioning.
• To explore the polypharmacological potential of existing drugs.
• To investigate drug repositioning opportunities for autoimmune diseases.

Main Methods:

• Screened over 500 kinases to identify B-cell inactivation targets.
• Utilized structure-based drug repositioning to analyze drug-target interactions.
• Investigated the interaction patterns of ibrutinib with BTK and VEGFR2.

Main Results:

• Identified 22 kinases that impede B-cell activation upon knockout.
• Discovered that the cancer drug ibrutinib inhibits VEGFR2 (KDR) with a high therapeutic index for B-cell inactivation.
• Confirmed ibrutinib's polypharmacological action beyond its designed target, Bruton's tyrosine kinase (BTK).

Conclusions:

• Ibrutinib exhibits polypharmacology by inhibiting both BTK and VEGFR2.
• Structure-based drug repositioning successfully identified ibrutinib as a VEGFR2 inhibitor, offering a cost-effective screening method.
• Ibrutinib shows potential for treating VEGFR2-associated diseases, including autoimmune conditions.