Synthesis and Evaluation of a Photoswitchable ABL Kinase Inhibitor as a Biochemical Tool

Abstract

With so much to learn about the various biological pathways that allow complex organisms to function, researchers are constantly working to expand their biochemical toolkit. A common way to study the role of an enzyme is to inhibit the protein with a drug and monitor effects such as metabolite buildup or increased activity in other enzymes. To assist these processes, the use of photoswitch molecules is beneficial. The electronics of these molecules allow them to change conformation in response to specific wavelengths of light. With the shape of a drug being so crucial to its binding affinity, molecules capable of changing their shape may be active in one conformation but inactive in the other. This allows these drugs to be activated and inactivated at will, allowing for more in‐depth studies of the spatial and temporal role of proteins. Azo‐stilbenes are among the most well established photoswitches. The azo‐stilbene structure, a chromophore commonly present in industrial dyes due to its vibrant colors, consists of two aromatic rings connected by an azo (N=N) bond. When irradiated with blue light (wavelength of 450–490 nm) these molecules undergo a trans‐to‐cis isomerization about the azo bond. Exposure to heat or red light (wavelength 620–750 nm) incites these molecules to relax back into their more thermodynamically favorable trans state. This poster will outline the synthesis and photophysical characterization of a photoswitchable inhibitor of ABL, a tyrosine kinase. A key component of the synthesis is the use of the Mills reaction, a condensation process that forms an azo bond between an amine and a nitroso compound. UV/Vis absorption spectroscopy was used to characterize properties such as the lambda max values for the cis and trans conformations as well as the thermal relaxation time. This molecule may also have potential for more targeted cancer treatments since the BCR‐ABL fusion gene causes chronic myeloid leukemia. By administering the drug in its inactive conformation and then irradiating sites to induce isomerization where cancer cells are present, unnecessary cell death may be avoided. Treatment of this sort could reduce the side effects of current CML treatments, namely low blood cell counts, which may result in infection and/or anemia.Support or Funding InformationAlbion College Foundation for Undergraduate Research, Scholarship, and Creative ActivitiesThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.