Design and Synthesis of a Photoisomerizable Second Generation Kinase Inhibitor

Abstract

BCR/ABL is a chimeric oncogene made up of breakpoint cluster region protein (BCR) from chromosome 22 and Abelson murine leukemia (ABL) from chromosome 9. This genetic recombination results in a shortened chromosome 22, which is also known as the Philadelphia Chromosome. The BCR/ABL fusion protein produced as a result of this translocation mutation causes the resulting tyrosine kinase enzyme to become constitutively active. Given the critical regulatory role of ABL in cell division, its constitutive activation results in uncontrollable cell division, which in this case, most often leads to chronic myeloid leukemia (CML). BCR/ABL has also been associated with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).The first‐generation treatments for diseases caused by this mutation were approved for use in 2001 and were kinase inhibitors. These inhibitors effectively shut off the dysfunctional kinase and shut down uncontrolled cell division. Over time, cancer cells can become resistant to drugs and many CML patients begin to experience resistance to first‐generation therapies. These resistances are caused by mutations in the target kinase, which change the drug binding site and/or protein conformation. Although the development of second‐generation therapeutics has addressed many of these issues, one common problem remains off‐target interactions of these drugs, which result in undesirable side effects. One way to address both of those issues is create drugs that can be switched on/off when and where necessary. Light can be used to change the shape of molecules. Since the shape of molecules is important for their binding to a biomolecule, changing shape can change bioactivity. The purpose of this research is to test the photo‐induced bioactivity of azologues of a second‐generation BCR/ABL inhibitor. Azologues are light activated versions of known biologically active molecules, whose photoisomerizable properties are imparted by the presence of an azo‐stilbene group. Compounds that can be selectively spatially and temporally activated by light could circumvent these off‐target interactions. Additionally, photoisomerizable molecules can be useful tools for investigating biological systems. Given the spatial and temporal control that photoisomerization allow, they may be utilized as powerful chemical tools for the study of time and location dependent cellular processes. The design and synthesis of the target molecule will be outlined as well as the unique synthetic challenges associated with this class of biomolecule.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.