Controlling Ibrutinib's Conformations about Its Heterobiaryl Axis to Increase BTK Selectivity

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor used in oncology, exhibits off-target activities causing adverse events.
• Existing medicinal chemistry efforts have yielded more selective BTK inhibitors, but new strategies are needed for rapid selectivity improvement.
• Analysis of Protein Data Bank (PDB) data revealed ibrutinib binds BTK in conformations orthogonal to its predicted low-energy range.

Purpose of the Study:

• To explore conformational control as a strategy for enhancing kinase inhibitor selectivity.
• To design and synthesize ibrutinib analogues with altered ground-state conformations.
• To assess the impact of conformational changes on BTK selectivity and off-target activities.

Main Methods:

• Analysis of existing Protein Data Bank (PDB) structures of ibrutinib bound to BTK.
• Computational prediction of ibrutinib's low-energy conformational range.
• Synthesis of novel ibrutinib analogues designed to adopt orthogonal conformations.
• Evaluation of the selectivity profile of synthesized analogues against BTK and other kinases.

Main Results:

• A series of ibrutinib analogues were synthesized with ground-state conformations shifted towards orthogonality.
• One analogue, featuring two incorporated ortho-methyl groups, demonstrated significantly increased selectivity for BTK.
• This suggests that controlling conformation around a potential atropisomeric axis can enhance target selectivity.

Conclusions:

• Conformational control around an atropisomeric axis is a viable strategy for rapidly improving kinase inhibitor selectivity.
• This approach offers a new avenue for developing more targeted and safer kinase inhibitors.
• The findings provide a foundation for designing next-generation inhibitors with enhanced selectivity profiles.