Presentation Title

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

Faculty Mentor

Jeffrey Gustafson

Start Date

23-11-2019 10:00 AM

End Date

23-11-2019 10:45 AM

Location

247

Session

poster 3

Type of Presentation

Poster

Subject Area

physical_mathematical_sciences

Abstract

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.

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.

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Nov 23rd, 10:00 AM Nov 23rd, 10:45 AM

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

247

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.

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.