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

Abstract

Ibrutinib is a covalent BTK inhibitor that is approved for several indications in oncology. Ibrutinib possesses significant off-target activities toward many kinases, often leading to adverse events in patients. While there have been robust medicinal chemistry efforts leading to more selective second-generation BTK inhibitors, there remains a need for new strategies to rapidly improve the selectivity of kinase inhibitors. An analysis of PDB data revealed that ibrutinib binds BTK in dihedral conformations that are orthogonal of ibrutinib's predicted low energy conformational range. Synthesis of a series of analogues with ground state conformations shifted toward orthogonality led to the discovery of an analogue with two incorporated ortho-methyl groups that possessed markedly increased BTK selectivity. This work suggests that conformational control about a prospective atropisomeric axis represents a strategy to rapidly program a compound's selectivity toward a given target.

Predisposition in Dynamic Covalent Chemistry: The Role of Non‐Covalent Interactions in the Assembly of Tetrahedral Boronate Cages

“…Conformation is a pivotal factor that significantly influences the biological and physico‐chemical properties of organic molecules. This impact is evident in various crucial functions, including catalysis, [1] molecular recognition, [2] the development of optoelectronic materials, [3] drug design, [4] and many more. A significant influence has also been observed in the design of building blocks for assembling diverse molecular architectures, such as molecular organic cages (MOCs) and covalent organic frameworks (COFs) [5] .…”

Conformational control enables boroxine-to-boronate cage metamorphosis

“…In this sense, the conformational control of molecules is a fundamental aspect of organic chemistry that supports the emergence of functions such as molecular recognition, 6 catalysis, 7 materials with optoelectronic properties, 8 drug design, 9 and more.…”