Development of a Polo-like Kinase‑1 Polo-Box Domain Inhibitor as a Tumor Growth Suppressor in Mice Models

• Published in: Journal of medicinal chemistry Vol. 63; no. 23; pp. 14905 - 14920
• Main Authors: Gunasekaran, Pethaiah, Yim, Min Su, Ahn, Mija, Soung, Nak-Kyun, Park, Jung-Eun, Kim, Jaehi, Bang, Geul, Shin, Sang Chul, Choi, Joonhyeok, Kim, Minkyoung, Kim, Hak Nam, Lee, Young-Ho, Chung, Young-Ho, Lee, Kyeong, EunKyeong Kim, Eunice, Jeon, Young-Ho, Kim, Min Ju, Lee, Kyeong-Ryoon, Kim, Bo-Yeon, Lee, Kyung S, Ryu, Eun Kyoung, Bang, Jeong Kyu
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.12.2020; Amer Chemical Soc
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Barbiturates - chemical synthesis; Barbiturates - metabolism; Barbiturates - pharmacokinetics; Barbiturates - therapeutic use; Carbocyanines - chemistry; Cell Cycle Proteins - antagonists & inhibitors; Cell Cycle Proteins - metabolism; Chemistry, Medicinal; Drug Design; Drug Screening Assays, Antitumor; Fluorescent Dyes - chemistry; G2 Phase Cell Cycle Checkpoints - drug effects; HeLa Cells; Humans; Life Sciences & Biomedicine; Male; Mice, Inbred BALB C; Mice, Inbred ICR; Molecular Structure; Neoplasms - diagnosis; Neoplasms - drug therapy; Pharmacology & Pharmacy; Polo-Like Kinase 1; Protein Binding; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Protein Serine-Threonine Kinases - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Science & Technology; Structure-Activity Relationship; Xenograft Model Antitumor Assays
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.0c01451

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 (t 1/2, 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.