Development of a Polo-like Kinase-1 Polo-Box Domain Inhibitor as a Tumor Growth Suppressor in Mice Models
P. Gunasekaran, Min Su Yim, Mija Ahn, Nak‐Kyun Soung, Jung‐Eun Park, Jaehi Kim, Geul Bang, Sang Chul Shin, Joonhyeok Choi, Minkyoung Kim, Hak Nam Kim, Young‐Ho Lee, Young‐Ho Chung, Kyeong Lee, Kyeong Lee, Eunice EunKyeong Kim, Young-Ho Jeon, Min Ju Kim, Kyeong‐Ryoon Lee, Kyeong‐Ryoon Lee, Bo-Yeon Kim, Kyung S. Lee, Kyung S. Lee, E. K. RYU, Jeong Kyu Bang
Abstract
Polo-like kinase-1 (Plk1) plays a key role in mitosis and has been identified as an attractive anticancer drug target. Plk1 consists of two drug-targeting sites, namely, N-terminal kinase domain (KD) and C-terminal polo-box domain (PBD). As KD-targeting inhibitors are associated with severe side effects, here we report on the pyrazole-based Plk1 PBD inhibitor, KBJK557, which showed a remarkable in vitro anticancer effect by inducing Plk1 delocalization, mitotic arrest, and apoptosis in HeLa cells. Further, in vivo optical imaging analysis and antitumorigenic activities in mouse xenograft models demonstrate that KBJK557 preferentially accumulates in cancer cells and selectively inhibits cancer cell proliferation. Pharmacokinetic profiles and partition coefficients suggest that KBJK557 was exposed in the blood and circulated through the organs with an intermediate level of clearance (t1/2, 7.73 h). The present investigation offers a strategy for specifically targeting cancer using a newly identified small-molecule inhibitor that targets the Plk1 PBD.