Discovery of novel KSP-targeting PROTACs with potent antitumor effects in Vitro and in Vivo

Kinesin spindle protein (KSP) plays a crucial role during mitosis, making it an attractive target for cancer treatment. Herein, we report the design, synthesis, and evaluation of the first series of KSP degraders by using the utilization of the proteolysis-targeting chimera (PROTAC) technology. Compound 21 was identified as a potent KSP degrader with a DC₅₀ (concentration causing 50% of protein degradation) value of 114.8 nM and a D_max (maximum degradation) of 90% in the HCT-116 cells. Compound 21 showed strong antiproliferative activity against HCT-116 cells with an IC₅₀ values of 10 nM. Mechanistic investigations revealed that 21 causes the cell arrest at the G2/M phase and subsequent cell apoptosis. In addition, 21 demonstrated more significant inhibition of tumor growth in an HCT-116 xenograft model compared to its parent compound 1. Our findings suggest that 21 may become the promising leads for further development.