What Aurora B inhibitors are in clinical trials currently?

Introduction to Aurora B KinaseAurora B B is one of the three members of the Aurora kinase family, which serve as critical regulators of mitosis. It plays a pivotal role in chromosome condensation, proper alignment at the metaphase plate, and cytokinesis. In many cell-based and in vivo models, inhibition of Aurora B has shown profound effects on cell division fidelity and tumor cell survival. Research from synapse-based publications clearly shows that defects in Aurora B function lead to chromosomal instability and polyploidy—phenomena that are frequently associated with tumorigenesis.

Function and Role in Cell Cycle

Aurora B localizes mainly to the centromere and later to the midzone during mitosis, forming a crucial part of the chromosomal passenger complex (CPC). The kinase activity of Aurora B is essential for ensuring correct kinetochore–microtubule interactions, and it coordinates the timing of cytokinesis (it ensures that sister chromatids are correctly segregated before cell division is completed). In addition, the enzyme phosphorylates substrates such as histone H3 (an accepted marker for Aurora B activity), and its inactivation often results in the failure to complete cytokinesis and subsequent formation of multinucleated cells. This precise regulation is vital in the cell cycle, ensuring that the genetic material is accurately transmitted to daughter cells.

Importance in Cancer Therapy

Aberrant expression and dysregulation of Aurora B have been widely observed in several types of cancer, including solid tumors and hematological malignancies. Overexpression of Aurora B is associated with chromosomal instability and has been implicated in the development of drug resistance, making it an enticing target for anticancer therapy. Since many conventional chemotherapies cause cell death by interfering with mitosis, selectively inhibiting Aurora B offers the promise of targeted therapies with improved therapeutic windows. Owing to its central role in mitosis, many pharmaceutical and academic teams have developed molecules that impair Aurora B activity. This may not only arrest tumor growth but also re-sensitize resistant tumors to chemotherapy.

Overview of Aurora B Inhibitors

Aurora B inhibitors have been designed both as pan-Aurora inhibitors and as molecules with a higher degree of selectivity for Aurora B over other isoforms, such as Aurora A. The rationale behind this selectivity is grounded in the observation that dual inhibition of Aurora A and B can lead to unwanted side effects due to toxicity, whereas selectively targeting Aurora B may favor a more acceptable safety profile and enable combination strategies with other anticancer agents.

Mechanism of Action

Aurora B inhibitors typically act by binding to the ATP-binding site of the kinase or, in some cases, by disrupting its interaction with essential co-factors (such as INCENP) within the CPC. By occupying the ATP-binding pocket, these inhibitors prevent Aurora B from phosphorylating key substrates such as histone H3. This inhibition in turn disrupts the regulation of chromosome alignment and cytokinesis, leading to errors during mitosis, prolonged mitotic arrest or induction of mitotic catastrophe, and ultimately apoptosis of rapidly dividing cancer cells. Importantly, the biochemical selectivity observed in vitro—such as a Ki in the sub-nanomolar range for Aurora B and markedly higher values for Aurora A—supports the therapeutic potential of selective inhibition.

Types of Aurora B Inhibitors

The current design strategies for Aurora B inhibitors have led to a few well-known classes. These include nucleotide mimetics (small molecules that mimic ATP), compounds with heterocyclic scaffolds designed to fit into the binding pocket, and novel allosteric inhibitors targeting protein–protein interactions. For instance, Barasertib (AZD1152) is a phosphate prodrug that is rapidly converted into an active form that selectively inhibits Aurora B with very low Ki (around 0.001 µM for Aurora B versus 1.4 µM for Aurora A), while other inhibitors such as BI 811283 have been demonstrated to selectively target Aurora B in advanced solid tumors. Some compounds identified via structure-based design have also been reported to disrupt the Aurora B–INCENP interaction, though these are primarily in preclinical development. In sum, despite the structural similarities between Aurora kinases, the design of inhibitors has evolved to yield molecules with a favorable selectivity profile for Aurora B, which may offer therapeutic advantages when used as single agents or in combination regimens.

Current Clinical Trials

When discussing the clinical landscape, it is important to note that many inhibitors developed preclinically have not advanced to clinical evaluation due to toxicity issues or suboptimal selectivity. Among the candidates that have successfully progressed into human trials, two molecules are among the most prominent Aurora B inhibitors currently in clinical trials.

Active Clinical Trials

The two leading Aurora B inhibitors in clinical trials that have emerged from synapse-based records are Barasertib (AZD1152) and BI 811283.

• Barasertib (AZD1152):
Barasertib is one of the earliest and most well-characterized selective Aurora B inhibitors developed. Derived from a series of quinazoline-based molecules, Barasertib has shown very potent inhibition of Aurora B activity in vitro and in vivo. Its active moiety exhibits a Ki in the sub-nanomolar range against Aurora B, and its selectivity profile has been established in multiple preclinical studies. Clinically, Barasertib has been explored in several early phase trials—especially in hematological malignancies such as acute myeloid leukemia (AML) as well as in some solid tumors. These trials aim to evaluate the maximum tolerated dose (MTD), safety profile (with a particular focus on hematological toxicities such as febrile neutropenia), and preliminary efficacy. Although some clinical studies with Barasertib have faced issues with toxicity and not reached later phase clinical trials, they provide crucial pharmacokinetic and pharmacodynamic data that inform the development of next-generation Aurora B inhibitors.

• BI 811283:
BI 811283 is another selective Aurora B inhibitor that has been evaluated in a phase I trial targeting advanced solid tumors. This molecule is administered via infusion (24-hour dosing on different schedule arms) and works by inhibiting Aurora B-mediated phosphorylation of histone H3—as measured by immunohistochemistry in surrogate tissues such as skin biopsies—as well as through assessments of apoptosis markers. In the phase I study mentioned in the synapse record, the maximum tolerated doses for BI 811283 were established, and dose-limiting toxicities were observed primarily in the hematological compartment (for example, neutropenia). Although no objective responses were reported at the initial doses, a number of patients achieved stable disease. The trial provided detailed pharmacodynamic evidence, confirming target engagement and thus validating the approach of selective Aurora B inhibition in cancer patients.

Additional compounds on the horizon in the clinical landscape are part of broader Aurora kinase inhibitor programs. Some clinical trial registries list agents that target both Aurora A and B, but for the purpose of answering our specific question regarding Aurora B inhibitors, Barasertib and BI 811283 are the most well-documented examples from synapse sources. There may be other early-phase candidates, such as some molecules administered in combination with chemotherapeutic regimens, but largely these two have clear dedicated clinical trial records as Aurora B–selective inhibitors.

Trial Phases and Objectives

The clinical trials of these Aurora B inhibitors are primarily in early phases, most notably Phase I/II studies. The following are some salient features about the trial design, endpoints, and objectives in these clinical studies:

• Dose Escalation and MTD Determination:
Phase I studies using compounds like BI 811283 are designed with dose-escalation cohorts to determine the maximum tolerated dose (MTD) and to pinpoint a biologically effective dose (BED) by correlating pharmacodynamic markers such as reduced levels of phosphorylated histone H3. Similar strategies have been applied to Barasertib studies, where dosing schedules (often continuous infusions or specified cycles) are evaluated to balance efficacy with adverse events, particularly hematologic toxicities.

• Pharmacodynamics and Biomarker Assessment:
Both compounds have been evaluated by measuring surrogate end points that indicate successful Aurora B inhibition. For instance, immunohistochemical detection of phosphorylated histone H3 in surrogate tissues is used to demonstrate target engagement. Additionally, changes in apoptosis markers (such as caspase-cleaved CK-18) have been monitored to provide evidence of the downstream cellular effects of Aurora B inhibition. These pharmacodynamic studies are complemented by detailed pharmacokinetic evaluations to understand spacing, drug exposure (AUC, Cmax), and metabolism.

• Preliminary Efficacy and Disease Stabilization:
Although early-phase clinical trials primarily concentrate on safety, stable disease outcomes and occasional partial responses have been observed; many of these studies target patients with advanced solid tumors or refractory hematologic malignancies who typically have limited treatment options. The primary objective is to assess if selective inhibition of Aurora B can result in durable disease stabilization or regression in patient subgroups that exhibit aberrant mitotic activity, which is supported by preclinical evidence.

Two key points on trial goals are (i) to define patient populations in which Aurora B dependency is most critical (for instance, patients with high levels of phosphorylated histone H3, or tumors with rapid proliferation rates) and (ii) to explore combination strategies with chemotherapy or targeted agents to overcome resistance mechanisms. Many of the trial designs incorporate biomarker-driven patient selection to maximize the likelihood of clinical benefit, which is an important consideration given the complexities of mitotic regulation in solid tumors versus hematologic malignancies.

Challenges and Future Directions

Even as these Aurora B inhibitors are advancing through clinical evaluation, several challenges remain that affect their long-term potential. The early clinical data offer promise, but also point to necessary areas for further investigation and optimization.

Clinical Challenges

One significant challenge observed in clinical trials of Aurora B inhibitors such as Barasertib and BI 811283 is toxicity. Because Aurora kinases are essential for normal mitosis, even selective inhibition can inadvertently affect rapidly dividing normal cells, notably within the hematopoietic compartment. This has resulted in dose-limiting toxicities such as febrile neutropenia and severe neutropenia in many studies. Furthermore, the narrow therapeutic window has been a hurdle, as higher doses that might confer better antitumor activity also increase the risk of adverse events.

Another challenge lies in patient selection. Tumors are heterogenous in their proliferative rates and in their reliance on Aurora B activity, making it difficult to predict which patients are likely to benefit most from these inhibitors. Biomarker studies, including measurement of phosphorylated histone H3 levels, are becoming a crucial component of trial design, but these assays remain technically challenging and require further standardization.

Drug resistance also presents a potential barrier. Cancer cells, known for their ability to adapt to targeted therapies, may eventually develop resistance mechanisms against Aurora B inhibition. These could involve mutations in the kinase domain or activation of compensatory pathways that allow for continued mitotic progression even in the presence of inhibitors. As such, combination therapy—with agents that target complementary pathways or overcome the specific resistance mechanisms—may be necessary to achieve lasting clinical benefits.

In addition, there is the challenge of designing dosing regimens that maintain sustained target inhibition while avoiding overt toxicity. Continuous infusion versus pulsatile dosing schedules are under investigation, but the optimal strategy is still unclear. The balance between efficacy and safety is critical and may require individualized dosing strategies based on pharmacokinetic/pharmacodynamic modeling.

Future Research and Development

Future research in the field of Aurora B inhibition is likely to focus on several key areas:

• Improving Selectivity and Potency:
Further chemical refinement of Aurora B inhibitors will be needed to maximize their selectivity and potency while minimizing off-target effects. Advances in structure-based drug design, coupled with high-throughput screening and QSAR modeling, will be instrumental in identifying next-generation inhibitors with an improved therapeutic window.

• Enhanced Biomarker Development:
Developing robust and reproducible biomarkers for target engagement is a priority. Assays that reliably measure phosphorylated histone H3 levels in both tumor tissue and surrogate tissues are essential for determining the effective doses in patients. Furthermore, integrating genomic or proteomic markers that predict Aurora B dependency could refine patient selection and improve trial outcomes.

• Combination Therapies:
Given the likelihood of resistance development and the limitations of monotherapy, future clinical strategies will probably involve combination regimens. Preclinical studies have already hinted at the synergistic effects of combining Aurora B inhibitors with chemotherapeutic agents (such as taxanes or irinotecan), radiation, or even immunotherapies in certain contexts. Future clinical trials may evaluate such combination strategies to enhance efficacy while potentially allowing for lower doses of each drug and thereby reducing toxicity.

• Optimizing Dosing Schedules:
Clinical research is also expected to explore alternative dosing schedules—from continuous infusions to intermittent dosing—to maximize target inhibition while mitigating toxicity. Advances in pharmacokinetic/pharmacodynamic modeling will help determine the best dosing regimens. Personalized dosing based on patient-specific parameters (such as baseline blood counts or metabolic profiles) may further optimize outcomes.

• Resistance Mechanisms and Second-Generation Inhibitors:
Understanding the molecular basis of resistance is critical. Future research might focus on second-generation inhibitors designed to bind to mutant forms of Aurora B that confer resistance or that target compensatory signaling pathways activated during Aurora B inhibition. Such strategies may include inhibitor cocktails or sequential treatment protocols to delay the emergence of resistant clones.

• Exploring New Indications:
While many current clinical trials are focused on advanced solid tumors and hematologic malignancies, there is also interest in evaluating Aurora B inhibitors in other tumor types where aberrant mitosis is a key driver of disease progression. Ongoing research may identify additional patient populations based on tumor proliferation indexes or specific molecular markers that correlate with Aurora B overactivity.

Conclusion

In summary, Aurora B inhibitors represent a promising class of targeted anticancer agents that disrupt key steps in the mitotic process. The function of Aurora B in ensuring correct chromosome alignment and cytokinesis makes it an appealing target—especially in tumors characterized by rapid proliferation and chromosomal instability. Among the Aurora B inhibitors that have been brought into clinical evaluation, Barasertib (AZD1152) and BI 811283 stand out as the leading candidates. Barasertib’s very high selectivity for Aurora B over Aurora A has allowed its investigation in early phase studies, particularly in hematologic malignancies and selected solid tumors, despite challenges with dose-limiting hematological toxicities. BI 811283, evaluated in a Phase I study, has provided critical pharmacodynamic data—using surrogate markers like phosphorylated histone H3—to demonstrate successful target engagement in patients with advanced solid tumors.

However, the clinical development of Aurora B inhibitors faces significant challenges, including toxicity due to their impact on normal dividing cells, the need for precise dosing regimens, limited patient selection criteria, and potential mechanisms of resistance that may curtail long-term efficacy. Future research is expected to concentrate on chemical refinements for improved selectivity, the development of reliable biomarkers for patient stratification, and combination protocols that can synergize with other anticancer modalities. Ultimately, overcoming these challenges will be essential to fully harness the potential of Aurora B inhibitors for cancer therapy.

This detailed analysis from multiple perspectives—from basic biology to clinical trial design—reflects the evolving landscape of Aurora B targeted therapy and demonstrates that while the journey is complex, current clinical trials (notably those testing Barasertib and BI 811283) lay the groundwork for further development. Continued efforts in refining these inhibitors, optimizing their delivery, and smartly integrating them with other treatments promise to provide new hope for patients with cancers driven by mitotic dysregulation.