Photoswitchable CENP-E Inhibitor Enabling the Dynamic Control of Chromosome Movement and Mitotic Progression

Abstract

Interfering with mitosis is a potential cancer therapy strategy. However, the lack of controllability of anti-mitotic drugs in cell growth suppression causes severe side effects and limits their clinical utility. Herein, we developed an azobenzene-based photoswitchable inhibitor of CENP-E, a mitotic kinesin required for chromosome transportation. The new inhibitor enabled reversible photoswitching of CENP-E activity with ~10fold change in IC50 between cis and trans photoisomerization states both in vitro and in living cells. It also enabled repeatable photoswitching of CENP-E-dependent chromosome congression and hence mitotic progression with UV/Vis light illumination cycles. Using this technique, we could specify the exact process of mitotic progression in which CENP-E plays an indispensable role. Our data demonstrate the power of photochemical approach for highly controllable mitotic interference as well as for discovery of precise molecular functions in dynamic cellular processes.

Light‐Triggered, Non‐Centrosymmetric Self‐Assembly of Aqueous Arylazopyrazoles at the Air–Water Interface and Switching of Second‐Harmonic Generation

“…For example, Ravoo and others reported aqueous cyclodextrin‐based host‐guest systems, [21–25] surfactant at the air–water interface, [26] supramolecular gels [27] . Arylazopyrazole derivatives have also been used as photoswitchable enzyme inhibitors [28, 29] …”

“…Although some studies on arylazopyrazole derivatives have been carried out in dilute aqueous solutions, [21–25, 28, 29] we focused on the photo‐induced solubility changes and aggregation of 1 , 2 in water at high concentrations. We expected hydrophilicity of the pyrazole group as it contains two polar covalent C−N bonds, and the N (2) atom can serve as a hydrogen bond acceptor for solvating water molecules.…”

Light-induced modulation of DNA recognition by the Rad4/XPC damage sensor protein

“…3,4 Such lightinduced chemical/structural conversions have emerged as useful tools to control the properties and hence probe the functions of biomolecules harboring the photoconvertible groups, as light can be easily applied to biological systems in vitro or in vivo to trigger specific events. [5][6][7][8][9] Photoconvertible modifications in small molecules, [10][11][12] oligonucleotides, 13 peptides, 14,15 and proteins (mostly enzymes) [16][17][18][19] have also been used to control and monitor a wide variety of biological outcomes including gene expression, enzyme activity, oligomerization states, cellular localization and immune responses.…”

Light-induced modulation of DNA recognition by the Rad4/XPC damage sensor protein

“…Such light-induced chemical/structural conversions have emerged as useful tools to control the properties and hence probe the functions of biomolecules harboring the photoswitchable groups, as light can be easily applied to biological systems in vitro or in vivo to trigger specific events [5][6][7][8][9] . Photoswitchable modifications in small molecules [10][11][12] , oligonucleotides 13 , peptides [14][15] , and proteins (mostly enzymes) [16][17][18][19] have also been used to control and monitor a wide variety of biological outcomes including gene expression, enzyme activity, oligomerization states, cellular localization and immune responses.…”