Novel photochromic inhibitor for mitotic kinesin Eg5 which forms multiple isomerization states

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Mitotic kinesin Eg5 is crucial for cell division and a validated cancer therapy target.
• Existing Eg5 inhibitors lack precise temporal and spatial control.
• Development of controllable Eg5 inhibitors is needed for targeted cancer treatment.

Purpose of the Study:

• To synthesize and characterize a novel photoresponsive inhibitor for Eg5.
• To investigate the multistage inhibitory activity of the inhibitor controlled by light.
• To establish a light-inducible system for precise control of Eg5 motor function.

Main Methods:

• Synthesis of a photochromic inhibitor, spiropyran-sulfo-azobenzene (SPSAB), incorporating spiropyran and azobenzene derivatives.
• Characterization of SPSAB isomerization states (SP-trans, MC-cis, MC-trans) induced by different light conditions.
• Assay of Eg5 ATPase and motor activities in the presence of different SPSAB isomers.

Main Results:

• SPSAB demonstrated three distinct photoisomerization states responsive to visible light, UV light, and dark conditions.
• Reversible changes in Eg5 ATPase and motor activities were observed, correlating with SPSAB photoisomerization.
• The SP-trans isomer exhibited the most potent Eg5 inhibition (IC50 = 30 µM), while MC-trans (IC50 = 38 µM) and MC-cis (IC50 = 86 µM) showed reduced activity.

Conclusions:

• A novel photochromic inhibitor (SPSAB) was successfully synthesized for precise control of Eg5.
• Light irradiation allows for tunable, multistage inhibition of Eg5 motor activity.
• This photoresponsive system offers a promising strategy for developing light-controlled anticancer drugs targeting Eg5.