Abstract: Acute Myeloid Leukemia (AML) is a heterogeneous and aggressive hematological malignancy that predominantly affects the elderly population. Standard intensive induction chemotherapy is often unsuitable for older or frail patients due to high mortality rates and severe toxicities, highlighting an urgent unmet clinical need for low-intensity, targeted therapies. Volasertib (BI6727) is a highly potent, selective, small-molecule inhibitor of Polo-like kinase 1 (Plk1), a critical regulator of the cell cycle and mitosis. By competitively binding to the ATP-binding pocket of Plk1, volasertib disrupts spindle assembly, induces prometaphase arrest (Polo arrest), and triggers apoptosis in leukemic cells. Preclinical and early-phase clinical trials demonstrated promising pharmacokinetic properties and significant antileukemic activity, particularly when combined with low-dose cytarabine (LDAC). However, recent Phase III data have revealed challenges regarding dose-limiting myelosuppression and overall survival benefits. This review comprehensively examines the pharmacological activity, molecular mechanism of action, structure-activity relationship, current limitations, and future perspectives of volasertib in the treatment of AML.
1. Introduction
Acute Myeloid Leukemia (AML) is a clonal hematological disorder characterized by the rapid proliferation of immature myeloid cells, leading to severe cytopenias, infections, and bleeding complications [2]. The median age of diagnosis is between 65 and 70 years. While younger, fit patients are typically treated with standard intensive induction chemotherapy (the "3+7" regimen of an anthracycline and cytarabine), this approach is often poorly tolerated by elderly and infirm patients, resulting in unacceptably high early mortality rates [1][2][4]. Consequently, there is a critical need for novel, low-intensity therapeutic strategies for this demographic.
The Polo-like kinases (Plks) are a family of serine/threonine protein kinases essential for cell cycle regulation. Plk1, in particular, is frequently overexpressed in various malignancies, including AML, and its overexpression correlates with poor prognosis and cellular proliferation [1][2]. Volasertib (BI6727) was developed as a highly selective, second-generation Plk1 inhibitor to target this pathway. Tailored to overcome the pharmacokinetic limitations of its predecessor, BI 2536, volasertib has been extensively investigated as a targeted therapy for AML patients ineligible for intensive chemotherapy [1][6].
2. Pharmacological Activity
Volasertib exhibits a highly favorable pharmacokinetic (PK) profile characterized by a long terminal half-life (approximately 111 to 135 hours), a large volume of distribution (over 3,000 to 4,000 L), and moderate clearance [1][2]. This profile ensures sustained tissue exposure and excellent penetration, which is critical for targeting rapidly proliferating leukemic cells in the blood and bone marrow [1][6].
In preclinical models, volasertib demonstrated potent anti-tumor activity across multiple human cancer cell lines and AML xenograft models, inducing tumor regression and delaying tumor growth [1][2]. Clinically, Phase I and II trials evaluated volasertib both as a monotherapy and in combination with low-dose cytarabine (LDAC) in AML patients. In a randomized Phase II trial for previously untreated AML patients ineligible for intensive therapy, the combination of volasertib and LDAC yielded an objective response rate (complete remission [CR] or CR with incomplete blood count recovery [CRi]) of 31.0%, compared to 13.3% for LDAC alone [1][2][4]. Furthermore, the combination significantly improved median event-free survival (5.6 vs. 2.3 months) and overall survival (8.0 vs. 5.2 months) [1][3]. Volasertib has also been investigated in combination with hypomethylating agents like decitabine, showing early signs of clinical activity (e.g., CR and partial responses) in older AML patients [3][4].
3. Molecular Mechanism of Action
Plk1 plays multiple indispensable roles during mitosis, including mitotic entry, centrosome maturation, bipolar spindle assembly, sister chromatid separation, and cytokinesis [2]. Volasertib exerts its primary mechanism of action by potently and selectively inhibiting the catalytic activity of Plk1. By blocking Plk1, volasertib disrupts normal mitotic progression, leading to a distinct cellular phenotype known as "Polo arrest" [1][6].
During Polo arrest, cells accumulate in the prometaphase of the cell cycle. This state is characterized by the formation of aberrant monopolar mitotic spindles that fail to attach properly to kinetochores, alongside the accumulation of phospho-histone H3 [1][2]. The inability to successfully navigate the spindle assembly checkpoint ultimately triggers apoptosis in the arrested leukemic cells [1][6]. Interestingly, while volasertib is highly specific to Plks, biochemical assays have shown that it can also inhibit the bromodomain and extraterminal (BET) family protein BRD4 at higher concentrations (e.g., 300 nM), though the clinical relevance of this secondary mechanism remains to be fully elucidated [1].
4. Structure-Activity Relationship (SAR)
Volasertib is a small-molecule, ATP-competitive kinase inhibitor belonging to the dihydropteridinone derivative class [1][2]. It was rationally designed and tailored from its predecessor, BI 2536, to optimize potency, kinase selectivity, and in vivo pharmacokinetic properties [1]. Structurally, volasertib targets the highly conserved ATP-binding pocket of Plk1. 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 Plk1 [6].
This structural configuration grants volasertib exceptional potency and selectivity. It exhibits a half-maximal inhibitory concentration (IC50) of 0.87 nM for Plk1, with slightly lower affinity for the closely related kinases Plk2 (IC50 = 5.0 nM) and Plk3 (IC50 = 56 nM) [1][2][6]. Importantly, volasertib shows no appreciable inhibitory activity against a broad panel of over 50 to 60 other unrelated kinases even at concentrations up to 10 μM, underscoring its high target specificity [1][2].
5. Current Limitations
Despite its robust preclinical and early clinical efficacy, the development of volasertib faces significant hurdles, primarily related to toxicity. Because Plk1 is essential for the division of all proliferating cells, volasertib's mechanism of action inherently affects normal hematopoietic progenitor cells, leading to severe myelosuppression [1][2]. The most common dose-limiting toxicities (DLTs) observed in clinical trials include Grade 3/4 neutropenia, thrombocytopenia, anemia, and febrile neutropenia. In some cases, this profound immunosuppression has led to fatal opportunistic infections, such as fungal pneumonia [2].
These safety concerns culminated in disappointing results during the Phase III POLO-AML-2 trial (NCT01721876), which compared LDAC plus volasertib against LDAC plus placebo in elderly AML patients. The trial failed to demonstrate a statistically significant improvement in the objective response rate for the volasertib arm. More critically, severe toxicity issues in the combination arm led to a trend toward inferior overall survival, dampening the initial enthusiasm for the drug [7]. Additionally, there is a notable lack of validated predictive biomarkers to identify which AML subpopulations are most likely to benefit from Plk1 inhibition, making patient stratification difficult [1].
6. Future Perspectives
The future utility of volasertib and other Plk1 inhibitors in AML relies heavily on optimizing therapeutic windows and identifying robust predictive biomarkers. Research into proteomics may uncover specific Plk1-phosphorylated proteins, p53 functional status, or downstream targets in the mTOR pathway that could predict sensitivity to volasertib, allowing for personalized treatment approaches [1].
Furthermore, combination strategies remain a vital avenue for investigation. Combining volasertib with epigenetic modifiers, such as the hypomethylating agents decitabine or azacitidine, is currently being explored in clinical trials to achieve synergistic antileukemic effects at potentially lower, less toxic doses [1][3]. The dual inhibition of Plk1 and BRD4—given volasertib's off-target BET inhibition at higher concentrations—also presents an intriguing concept that could be exploited alongside other epigenetic therapies [1]. Ultimately, refining dosing schedules to mitigate myelosuppression while maintaining anti-leukemic efficacy will be paramount in determining the clinical viability of volasertib in AML management.
