An investigation of Plk1 PBD inhibitor KBJK557 as a tumor growth suppressor in non-small cell lung cancer

Abstract

Lung cancer is the second most commonly reported type of cancer worldwide. Approximately 80–85% of lung cancer occurrences are accounted by non-small cell lung cancer (NSCLC). Polo-like kinase-1 (Plk1) plays multiple roles in cell cycle progression and its overexpression is observed in majority of malignancies, including NSCLC. A combination of frontline drugs and inhibitors targeting the Plk kinase domain (KD) has been used to overcome drug resistance in NSCLC. Plk1 KD inhibitors are highly prone to cross-reactivity with similar kinases, eventually leading to undesirable side effects. Moreover, there have been no reports of Plk1 PBD inhibitors showing antitumorigenic effects on NSCLC cells or animal models so far. To address this issue herein, for the first time, our recently reported Plk1 PBD inhibitor KBJK557 was evaluated for the anticancer potential against NSCLC cells. KBJK557 displayed notable cytotoxic effects in A549, PC9, and H1975 cells. Mechanistic investigations revealed that KBJK557-treated cells underwent G2/M cell cycle arrest, triggering subsequent apoptosis. In vivo antitumorigenic activity in xenograft mice model demonstrates that KBJK557-treated mice showed a considerable decrease in tumor size, proving the significances of Plk1 in lung cancer. Collectively, this study demonstrates that KBJK557 can serve as a promising drug candidate for treating the lung cancer through Plk1 PBD inhibition.

Anticancer Activity of Anti-Tubercular Compound(s) Designed on Pyrrolyl Benzohydrazine Scaffolds: A Repurposing Study

“…In accordance with our findings, several earlier studies have also reported the cell cycle arrest of cancer cells at the DNA damage G2/M checkpoint and apoptosis after PLK1 inhibition [58][59][60]. In fact, strong PLK1 associations with the A549 cells [61][62][63] further strengthen the outcomes. However, it is too early to provide the conclusive remark on the applicability of C8 as a dual therapeutic agent for tuberculosis and lung cancer.…”

Degradation of Polo-like Kinase 1 by the Novel Poly-Arginine N-Degron Pathway PROTAC Regulates Tumor Growth in Nonsmall Cell Lung Cancer

“…For instance, evaluation of PLK1 expression level in NSCLC cell lines, including A549, PC9, and H1975 showed a significant PLK1 level similar to that of HeLa cells in Western blots (Figure S6). , Based on the aforementioned facts and inspired by the prominent potency of DD-2 against HeLa cells, we intended to investigate the degradation of the PLK1 in those NSCLC cell lines, as shown in Figure e–g.…”

“…In the past few decades, considerable efforts have been devoted to the discovery of several kinase domain targeting inhibitors, including GSK461364, BI2536, volasertib, ON 01910, NMS-P937, and TAK-960 ,− and promoted to clinical trials. However, most of the inhibitors fail to cross clinical phase trail-II due to the cross-reactivity that arises from a high degree of homogenicity of ATP binding pockets in various kinases. , Alternatively, targeting the unique allosteric site (PBD) of PLK1 was found to be a valid strategy to overcome the cross-reactivity and subsequent side effects. , Many research groups, including our group, have made significant breakthroughs in the discovery of peptide and small molecule-based PLK1 PBD inhibitors. , …”