Abstract: Volasertib (BI6727) is a highly potent and selective small-molecule inhibitor of Polo-like kinase 1 (Plk1), a critical regulator of the cell cycle. Originally developed to overcome the pharmacokinetic limitations of its predecessor, BI 2536, volasertib has demonstrated significant preclinical and clinical activity across various malignancies. In the context of advanced solid tumors, volasertib induces mitotic arrest (termed "Polo arrest") and subsequent apoptosis by disrupting spindle assembly. Clinical trials have shown that volasertib possesses a favorable pharmacokinetic profile, characterized by a long half-life and large volume of distribution, allowing for excellent tissue penetration. While single-agent efficacy in advanced solid tumors has been modest, partial responses and stable disease have been observed in heavily pretreated patients with melanoma, urothelial, ovarian, and non-small cell lung cancers. Current research is heavily focused on combination therapies and the identification of predictive biomarkers to optimize patient selection and overcome dose-limiting hematological toxicities. This review synthesizes the pharmacological, mechanistic, and clinical data surrounding volasertib, highlighting its potential and future directions in the management of advanced solid tumors.
1. Introduction
The Polo-like kinases (Plks) are a family of serine/threonine protein kinases that play integral roles in cell cycle regulation, including entry into mitosis, DNA replication, and the stress response to DNA damage [1][2]. Among the mammalian Plks, Plk1 is the most extensively studied and is considered a highly attractive therapeutic target in oncology. Plk1 is frequently overexpressed in a wide variety of malignancies, including non-small cell lung cancer (NSCLC), breast, prostate, colorectal, ovarian, and head and neck cancers, as well as melanoma and acute myeloid leukemia (AML) [1][2]. This overexpression is often correlated with poor prognosis, advanced disease stage, higher histologic grade, and increased metastatic potential [1].
Early efforts to target Plk1 led to the development of BI 2536, a first-generation inhibitor that validated Plks as drug targets but ultimately demonstrated modest clinical activity in solid tumors due to a suboptimal pharmacokinetic (PK) profile, specifically a short terminal half-life and low intratumoral exposure [1]. To address these limitations, volasertib (BI6727) was discovered and developed. Volasertib is currently one of the most clinically advanced investigational Plk inhibitors. While it has shown particularly promising results in AML, its development has also been extensively pursued in advanced solid tumors, where it has demonstrated broad antitumor activity and an improved PK profile [1][5].
2. Pharmacological Activity
Volasertib exhibits potent pharmacological activity both in vitro and in vivo. Preclinical evaluations demonstrated that volasertib potently inhibits cellular proliferation across a multitude of cancer cell lines, including colon, lung, melanoma, and various pediatric tumors [1][2]. In human tumor xenograft models (e.g., colon, NSCLC, and taxane-resistant colon cancer), volasertib monotherapy induced significant tumor growth delays and regressions [1][2][5]. Pharmacokinetic analyses in these models revealed a high volume of distribution, indicating excellent tissue penetration, and a long terminal half-life, which supported its clinical advancement [1][5].
In human clinical trials for advanced solid tumors, volasertib's favorable PK profile was confirmed. Phase I studies reported a large volume of distribution (>3,000 to 4,000 L), moderate clearance, and a long terminal half-life ranging from 107 to 135 hours [1][2]. The first-in-human trial in patients with progressive metastatic solid tumors revealed signs of antitumor activity, with partial responses (PRs) observed in patients with urothelial cancer, ovarian cancer, and melanoma, alongside a high rate of stable disease despite heavy pretreatment [1][2]. Subsequent Phase II trials further evaluated its efficacy. In a study of 50 patients with metastatic urothelial cancer following platinum failure, volasertib achieved a 14% PR rate and a 26% stable disease rate [1]. In advanced ovarian cancer, single-agent volasertib showed antitumor activity comparable to investigator's choice chemotherapy [1]. Furthermore, volasertib has been investigated in combination with other agents, such as afatinib, nintedanib, and pemetrexed, to enhance its pharmacological efficacy in refractory solid tumors [1][4].
3. Molecular Mechanism of Action
Volasertib functions as a highly selective, ATP-competitive kinase inhibitor [1][2]. It targets the catalytic domain of Plk1, which is responsible for the enzyme's serine/threonine kinase activity [2]. By binding to the ATP-binding pocket, volasertib prevents Plk1 from phosphorylating its downstream substrates, which are essential for multiple stages of mitosis, including mitotic entry, centrosomal maturation, spindle assembly, and cytokinesis [2].
The inhibition of Plk1 by volasertib leads to a distinct cellular phenotype known as "Polo arrest." Cells treated with volasertib fail to form normal bipolar mitotic spindles; instead, they accumulate in the prometaphase of the cell cycle with aberrant monopolar spindles [1][2][5]. In this arrested state, kinetochores are inappropriately attached to the spindle, and there is an accumulation of phospho-histone H3 [1]. Because the cells cannot successfully complete cell division, this prolonged mitotic arrest ultimately triggers apoptosis (programmed cell death) [1][2]. Importantly, preclinical studies suggest that volasertib's apoptotic effects are highly pronounced in rapidly proliferating tumor cells, while normal, non-neoplastic cells (such as normal intestinal cells in mice) appear less affected [5].
4. Structure-Activity Relationship (SAR)
Volasertib belongs to the dihydropteridinone class of small-molecule compounds [1][2][5]. It was discovered through the screening of organic compound libraries and was specifically tailored from the chemical structure of the first-generation inhibitor, BI 2536 [1][2]. The structural modifications in volasertib were rationally designed to optimize potency, kinase selectivity, and in vivo efficacy, while specifically addressing the rapid metabolism and short half-life that limited BI 2536 [1].
Structurally, volasertib targets the highly conserved ATP-binding pocket of the Plk enzymes. It binds to the hinge region located between the amino-terminal and carboxyl-terminal lobes of the kinase domain. This binding is stabilized through critical hydrogen bonds formed between the dihydropteridinone core of volasertib and the backbone amino and carbonyl groups of the Cys133 residue in human Plk1 [5]. Because the ATP-binding pocket is highly conserved among the Polo-like kinase family, volasertib also inhibits Plk2 and Plk3, though with significantly lower affinity. The half-maximal inhibitory concentration (IC50) of volasertib is exceptionally potent for Plk1 at 0.87 nM, compared to 5.0 nM for Plk2 and 56 nM for Plk3 [2][5]. It exhibits no appreciable inhibition against a panel of over 60 other unrelated kinases at concentrations up to 10 μM, underscoring its high selectivity [1][2].
5. Current Limitations
Despite its potent preclinical profile, the clinical application of volasertib in advanced solid tumors faces several limitations. First, while some patients achieve prolonged responses, the overall single-agent antitumor activity in solid tumors has been modest [1]. This may be partly due to the heterogeneous blood supply and elevated interstitial pressure in solid tumors, which can limit drug distribution despite volasertib's large volume of distribution [1]. Furthermore, solid tumors generally have a lower mitotic index compared to hematological malignancies like AML, potentially making them less susceptible to cell cycle-specific inhibitors [1].
Second, the safety profile of volasertib is characterized by significant, dose-limiting hematological toxicities. Across multiple clinical trials, the most common Grade 3/4 adverse events (AEs) were reversible neutropenia, thrombocytopenia, febrile neutropenia, and anemia [1][2]. Meta-analyses of Plk1 inhibitors confirm that the incidence of AEs is most prominent in the hematological system, which can complicate dosing and patient compliance [3]. Other reported dose-limiting toxicities include fatigue, weight loss, and QT prolongation [2].
Finally, there is a critical lack of validated predictive biomarkers. Currently, it is difficult to identify which patients with solid tumors are most likely to respond to volasertib, leading to unselected patient populations in trials and diluted efficacy signals [1].
6. Future Perspectives
The future development of volasertib in advanced solid tumors relies heavily on two main strategies: combination therapies and biomarker discovery. Because single-agent efficacy is modest, combining volasertib with other therapeutic modalities is a highly active area of research. Clinical trials have already begun exploring volasertib in combination with platinum-based chemotherapy, as well as targeted agents like the EGFR inhibitor afatinib and the angiokinase inhibitor nintedanib [1][4]. Preclinical data also suggest synergistic potential when combining Plk1 inhibitors with microtubule-destabilizing drugs (e.g., vincristine or paclitaxel), mTOR inhibitors, and epigenetic modulators (e.g., HDAC or BET inhibitors) [4][6]. These rational combinations may help overcome intrinsic resistance and enhance tumor cell apoptosis.
Equally important is the identification of predictive biomarkers to guide patient selection. Proteomic analyses have identified numerous Plk1-phosphorylated proteins that could serve as markers of sensitivity [1]. Additionally, the genetic landscape of the tumor, such as p53 status or BRCA2 mutations, may influence susceptibility to Plk1 inhibition, though the exact relationships remain complex and require further elucidation [1]. Future clinical trials should incorporate comprehensive genomic and proteomic profiling to identify signatures that predict response, thereby enabling a personalized medicine approach for the use of volasertib in advanced solid tumors.
