Kinases are proteins that control biochemical pathways and if mutated or overexpressed, they can lead to serious diseases such as cancer. Therefore, many medicinal chemists focus on designing kinase inhibitors that attenuate the unregulated signaling. However, due to many kinases having very similar active binding sites, many inhibitors have off-target inhibition which can lead to undesirable side effects.<br/>Modern small molecule inhibitors contain many bi-aryl bonds, leading to instances of atropisomerism. Atropisomerism is a form of chirality that arises from hindered rotation about a bi-aryl bond. Another consequence of hindered bond rotation is a narrow range of low energy dihedral angles accessible to the molecule. We hypothesize that kinase inhibitors bind their target at specific dihedral angles depending on the kinase, and by controlling the dihedral angle of a kinase inhibitor, we can increase the selectivity of the inhibitor to its target.<br/>We wanted to apply this hypothesis to design an inhibitor of a specific kinase, Bruton’s tyrosine kinase (BTK). BTK is a kinase involved in B cell development and is a major player in types of leukemia and lymphoma. This has lead to several FDA-approved BTK inhibitor drugs, including Ibrutinib, a potent inhibitor that covalently targets a cysteine residue in the binding site of BTK to irreversibly bind the kinase. Unfortunately, Ibrutinib strongly binds to other kinases with similar cysteine residues, causing it to be fairly unselective. To test our hypothesis, we designed several analogs of Ibrutinib, all of which hinder the rotation of the main biaryl bond and narrow the dihedral window. We found that with our lead compound, which added two bulky methyl groups, we gained selectivity towards BTK compared to Ibrutinib, despite a small loss of potency. We also noticed through computational studies, that introducing the methyl groups causes steric strain between the methyl and the acrylamide, the motif that targets the cysteine. This causes the acrylamide to face away from the cysteine, greatly reducing its ability to form the covalent bond. To solve this issue, we inverted the point chiral center from (R) to (S) forcing the acrylamide to face towards the cysteine. Our hypothesis was proven accurate when the (S) analog displayed a 10x increase in potency towards BTK. Our future goal is to create more modifications to the Ibrutinib scaffold to increase potency while maintaining selectivity.

Controlling Ibrutinib's conformational space to design a more selective inhibitor

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.