Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor

Abstract

Considering the important side effects of conventional microtubule targeting agents, more and more research focuses on regulatory proteins for the development of mitosis-specific agents. Polo-like kinase 1 (Plk1), a master regulator of several cell cycle events, has arisen as an intriguing target in this research field. The observed overexpression of Plk1 in a broad range of human malignancies has given rise to the development of several potent and specific small molecule inhibitors targeting the kinase. In this review, we focus on volasertib (BI6727), the lead agent in category of Plk1 inhibitors at the moment. Numerous preclinical experiments have demonstrated that BI6727 is highly active across a variety of carcinoma cell lines, and the inhibitor has been reported to induce tumor regression in several xenograft models. Moreover, volasertib has shown clinical efficacy in multiple tumor types. As a result, Food and Drug Administration (FDA) has recently awarded volasertib the Breakthrough Therapy status after significant benefit was observed in acute myeloid leukemia (AML) patients treated with the Plk1 inhibitor. Here, we discuss both preclinical and clinical data available for volasertib administered as monotherapy or in combination with other anticancer therapies in a broad range of tumor types.

Mutations of the LIM protein AJUBA mediate sensitivity of head and neck squamous cell carcinoma to treatment with cell-cycle inhibitors

“…This is consistent with the results of clinical trials of treatment with PLK1 inhibitors in patients with solid tumors, which demonstrated striking clinical responses but low response rates (4–14%) and stable disease rates of 26–42% in unselected patients [41, 45–48, 53, 60]. Up to 11% of patients had stable disease for more than a year [45, 48].…”

Discovery of BPR1K871, a quinazoline based, multi-kinase inhibitor for the treatment of AML and solid tumors: Rational design, synthesis, in vitro and in vivo evaluation

“…It should be noted that several kinase inhibitors have been administrated as an iv infusion in clinical trials [39]. For example, volasertib, an intravenous polo-like kinase (PLK) inhibitor, is currently in phase III for the treatment of AML [40]. A phase II/III trial using barasertib (an intravenous AURKB inhibitor) alone and in combination with low dose cytosine arabinoside has been completed in AML [41].…”

PLK1, A Potential Target for Cancer Therapy

“…Several preclinical experiments have demonstrated that BI6727 is highly efficacious in inducing tumor regression [116], [132], [133], [134]. As a result, this agent has recently been awarded the “Breakthrough Therapy Status” by the Food and Drug Administration for its significant benefit in treating acute myeloid leukemia patients [135]. However, because of the high conservation of ATP binding domains of different kinases and the frequent mutation in ATP binding sites, cancer patients always develop resistance to ATP -competitive inhibitors [136].…”