barasertib-HQPA (AZD2811) / AstraZeneca, Pfizer - LARVOL DELTA

Potentiating antitumoral type 1 interferon immune signaling in triple-negative breast cancer (TNBC) via combination treatment of Aurora kinase B (AURKB) inhibition and radiation therapy (AACR 2025) - "Here, we examined the effects of combined RT and AURKB inhibition on T1IFN signaling in TNBC. The half-maximal inhibitory concentrations (IC50) were calculated using cell viability assays with the treatment of AURKB inhibitors Barasertib-HQPA and SP-96 in human and murine TNBC cells... AURKB inhibition and RT induces T1IFN signaling in human and murine TNBC cells. Combination treatment also induces micronuclei formation, suggesting an upstream mechanism for the observed T1IFN signaling. These data suggest that AURKB inhibition and RT may be a promising strategy for the treatment of TNBC and can modulate the tumor immune microenvironment."

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AURKB • CXCL10 • IFNB1 • PD-L1

Patient-derived organoids as a screening platform to identify mechanisms of osimertinib resistance in non-small cell lung cancer (AACR 2025) - "The c-MET inhibitor capmatinib was specifically potent in LPTO245 but not in other models. This finding was confirmed using savolitinib, another selective c-MET inhibitor, suggesting the observed effects were due to on-target c-MET inhibition...Additionally, we identified an inverse sensitivity correlation between osimertinib and the Aurora kinase B inhibitor AZD2811 across all 6 models (r = -0.64; p = 0.03)... Our screening platform can provide novel biological insights into osimertinib resistance. Moreover, it can potentially identify drug combinations with immediate clinical utility in NSCLC, particularly with approved and clinical-grade drugs."

Clinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • AURKB • BRD4 • CDK4 • EGFR • PLK1 • ROS1

TAZMAN: Study of AZD2811 + Durvalumab in ES-SCLC (clinicaltrials.gov) - P2 | N=31 | Active, not recruiting | Sponsor: AstraZeneca | Trial completion date: Mar 2023 ➔ Dec 2025

Trial completion date • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

Co-inhibition of Aurora kinase B and SUV4-20H induces synthetic lethality in Wild-type p53 deficient cancer cells. (PubMed, Mol Cancer Ther) - "Barasertib (AZD2811) targets the mitotic kinase Aurora B (AURKB) and is in current clinical trials for various cancers. Lastly, we found in two different p53 mutated cell line tumor models that barasertib plus A196 has greater anti-tumor activity than either single agent. Our results suggest co-targeting of AURKB and SUV4-20H1/2 could be effective against p53-mutated or deficient cancers, including TNBCs in which approximately 80% of cases are p53 mutated."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AURKB • TP53

High-throughput screening identifies Aurora kinase B as a critical therapeutic target for Merkel cell carcinoma. (PubMed, Nat Commun) - "In mice, AZD2811 nanoparticles inhibit tumor growth and increase survival in both VP-MCC and VN-MCC xenograft models. Overall, our unbiased screens identify AURKB as a promising therapeutic target and AZD2811NP as a potential treatment for MCC."

Journal • Genetic Disorders • Merkel Cell Carcinoma • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Solid Tumor • AURKB

Unraveling the molecular landscape of non-small cell lung cancer: Integrating bioinformatics and statistical approaches to identify biomarkers and drug repurposing. (PubMed, Comput Biol Med) - "Finally, seven repurposed candidate drugs ENTRECTINIB, SORAFENIB, CHEMBL1765740, TOZASERTIB, NERVIANO, AZD-1152-HQPA, and SELICICLIB were proposed through molecular docking analysis. In conclusion, the findings of this study have the potential to significantly impact the early diagnosis, prognosis, and treatment of NSCLC."

Biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • AURKA • CCNA2 • CCNB1

1H-19F cross-polarization magic angle spinning dynamic nuclear polarization NMR investigation of advanced pharmaceutical formulations. (PubMed, J Magn Reson) - "We use these sequences to study AZD2811, which is an active pharmaceutical ingredient (API), in its pure dry state as well as in its corresponding drug delivery formulation consisting of drug-loaded polymeric nanoparticles (PNPs)...The indirect 19F DNP enhancement εon/off(19F) = 26 was obtained via 1H-19F CP for the pure API impregnated with DNP solution, with an overall 30-fold sensitivity gain compared to the direct-detected 19F experiment under similar conditions. DNP enhancement value of εon/off(19F) = 42 was obtained via 1H-19F CP for the polymeric nanoparticle suspension and εon/off(19F) ≈ 150 were obtained for two different siRNAs in frozen DNP solution."

Journal

Aurora kinase B is required for growth and expansion of medulloblastoma cells in the tissue context. (PubMed, Neoplasia) - "We validated tumor suppressive activities of the AURKB inhibitor (AURKBi) Barasertib (AZD1152-HQPA) and the structurally unrelated compound GSK-1070916 in cerebellum slice culture models for SHH, and Grp3 MB...We revealed that the combination of AURKBi with the SRC/BCR-ABL inhibitor Dasatinib acts synergistically to repress tumor growth and expansion in the highly invasive MB cell model ONS-76, but not in Grp3 MB cells...In conclusion, we demonstrate that AURKB is essential for MB tumor growth and expansion in the tissue context and the inhibition of AURKB is equally efficient as irradiation in repressing tumor cell growth. In patients younger than three years, pharmacological targeting of AURKB may thus constitute a novel means to overcome radiotherapy limitations."

Journal • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • ABL1 • AURKB • BCR

Differential regulation of expression of the protein kinases DYRK1A and DYRK1B in cancer cells. (PubMed, Sci Rep) - "Consistently, AURK inhibitors VX-680 (tozasertib), MLN8237 (alisertib), AZD1152-HQPA (barasertib) resulted in the upregulation of DYRK1B expression in A549 cells. In summary, our findings indicate that the expression of DYRK1A and DYRK1B is differentially regulated in cancer cells and reveal that the kinase inhibitor XMU-MP-1 increases DYRK1B expression likely through off target inhibition of Aurora kinases."

Journal • Oncology • AURKA • AURKB • DYRK1A • DYRK1B

Drug-induced senescence by aurora kinase inhibitors attenuates innate immune response of macrophages on gastric cancer organoids. (PubMed, Cancer Lett) - "It was found that DGCs showed drug-induced senescent phenotype after treatment by aurora kinases inhibitors (AURKi) Barasertib-HQPA and Danusertib. The up-regulation of local MCP-1/CCL2 can interact with MCP-1/CCL2 receptor (CCR2) expressed on macrophages and suppress their innate immunity to cancer cells. Overall, the special response of DGC to AURKi suggests that clinicians should select a sequential therapy with senescent cell clearance after AURKi treatment for DGC."

Journal • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • CCL2 • CCR2

Proteomic evaluation of combination data in acute myeloid leukemia to inform mechanism of action and new targets (AACR 2024) - "In the proteomics evaluation study, MOLM13 cells treated for 7 days under different conditions - (1) vehicle control; (2) cytarabine alone; (3) decitabine alone; (4) venetoclax alone; (5) AZD4573 alone; (6) AZD4573+cytarabine; (7) AZD4573+decitabine; (8) AZD4573+venetoclax - were collected for proteomics analysis using LC-MS/MS...Interestingly, targeting AURKB with AZD2811 has been shown to overcome venetoclax resistance in AML... Our proteomics analysis identifies vulnerable and resistant pathways and proteins, shedding light on the mechanism of action and revealing potential new targets for AML."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • AURKB • CDK9 • PHGDH

Targeting aurora kinase B (AURKB) as a radiosensitizing strategy in syngeneic models of triple negative breast cancer (TNBC) (AACR 2024) - "Here, we examined the effects of AURKB inhibition as a novel radiosensitizing strategy in syngeneic TNBC models. Cell viability assays were used to determine the half-maximal inhibitory concentrations (IC50) of the AURKB inhibitors Barasertib-HQPA and SP-96 72 hours post treatment... AURKB inhibition induces radiosensitization in syngeneic models of TNBC and leads to increased micronuclei and aneuploidy, suggesting a mechanism of sensitization. These results suggest that AURKB is a potential radiosensitizing strategy for the treatment of triple negative disease. Ongoing studies are further refining the underlying mechanisms of AURKB inhibition and RT on the antitumoral immune response."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • AURKB

Antineoplastic effects of pharmacological inhibitors of aurora kinases in CSF3R-driven cells. (PubMed, Blood Cells Mol Dis) - "In the present study, the cellular and molecular effects of pharmacological inhibitors of aurora kinases, such as aurora A inhibitor I, AZD1152-HQPA, and reversine, were evaluated in Ba/F3 expressing the CSF3R mutation...Reversine more efficiently modulated genes associated with cell cycle and apoptosis compared to other drugs. In summary, our findings shed new insights into the use of AURKB inhibitors in the context of CNL."

Journal • Chronic Neutrophilic Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • Oncology • ABL1 • AURKA • AURKB • CSF3R • STAT5

Targeting BCL2 overcomes resistance and augments response to aurora kinase B inhibition by AZD2811 in small cell lung cancer. (PubMed, Clin Cancer Res) - "BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models."

IO biomarker • Journal • Lung Cancer • Neuroendocrine Tumor • Oncology • Small Cell Lung Cancer • Solid Tumor • AURKB • BCL2 • MYC

Targeting BCL2 overcomes resistance and augments response to aurora kinase B inhibition by AZD2811 in small cell lung cancer (Clin Cancer Res) - "AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression....AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax..."

Preclinical • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer

Large scale pan cancer drug combination screening to identify effective and actionable combinations and biomarker hypothesis (AACR 2023) - "We selected 4 combinations based on clinical need and validated them further in vitro and in vivo (selumetinib plus venetoclax or AZD5991, AZD2811 plus venetoclax, and capivasertib plus AZD5991).To understand how molecular context affects drug response, we also used GDSC tools ANOVA to perform over 5.4 million statistical tests to identify statistically significant associations between drug response metrics and multi-omics features including mutations, CNAs, gene expression and methylation. This resulted in identification of 1,631 ‘emergent’ biomarkers.In summary, our screen and pipeline have been designed to optimize preclinical interpretation with a focus on actionability, particularly by our unique approach, and to provide a valuable resource for exploration by the wider research community. As a result of this screen, we identified and validated novel combination-tumor types in multiple cancer types."

Biomarker • IO biomarker • Pan tumor • Acute Myelogenous Leukemia • Diffuse Large B Cell Lymphoma • Endometrial Cancer • Oncology • Solid Tumor • AURKB • BRAF • KMT2D • KRAS • MLL2 • PIK3CA • PTEN • TP53

Modeling bladder cancer in Down Syndrome animals for discovery of novel therapeutics (AUA 2023) - "We evaluated drug sensitivity in a set of BCa cell lines using the AURKB specific inhibitor barasertib-HQPA... Our results indicate Ts65Dn mice have reduced tumor formation when exposed to BBN. Using Ts65Dn mice as a model may be a means for finding new drug targets as demonstrated by our results targeting AURKB."

Bladder Cancer • Developmental Disorders • Genetic Disorders • Genito-urinary Cancer • Hematological Disorders • Hematological Malignancies • Oncology • Solid Tumor • Urothelial Cancer • AURKB

A Phase I/II Study of AZD2811 Nanoparticles (NP) As Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory AML/MDS Patients Not Eligible for Intensive Induction Therapy (ASH 2019) - P1/2; "AurK B inhibitor AZD1152 (barasertib) showed benefit (35% CR/CRi) in patients (pts) with untreated AML when given as a 7-day continuous infusion (Lowenberg B et al, Blood 2011, Kantarjian HG et al., Cancer 2013). AZD2811NP is documented to be well tolerated at doses up to 600 mg on Day 1 & 4 every 28 days in monotherapy setting and up to 400 mg (D1 & 4) in combination with azacitidine. The monotherapy and combination therapy dose escalations are ongoing. Updated results including preliminary efficacy data will be presented."

Clinical • Monotherapy • P1/2 data • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Immunology • Myelodysplastic Syndrome • Neutropenia • Oncology • Septic Shock

SUKSES (Small Cell Lung Cancer Umbrella Korea Studies): A Phase II Biomarker-Driven Umbrella Study in Relapsed or Refractory SCLC (IASLC-WCLC 2018) - P=N/A; "Following treatment is applied after allocation: Arm-A (AZD5363); arm-B (Olaparib); arm-C (AZD1775); arm-D (AZD2014); arm-N1 (AZD1775); arm-N2 (Olaparib and AZD6738); arm-N3 (AZD2811). Arm N2 is under review by Institutional Review Board. Result Section not applicable Conclusion Section not applicable "

Biomarker • BRCA Biomarker • P2 data • PARP Biomarker • Small Cell Lung Cancer

Preclinical and Early Phase 1 Clinical Data of AZD2811 Nanoparticle in AML, an Aurora B Kinase Inhibitor (ASH 2017) - P1,P1/2; "Based on the promising clinical proof of principle data with AZD1152 and the preclinical evidence for AZD2811 nanoparticle, a clinical phase 1/2 study in elderly patients with newly diagnosed AML who are unfit for standard induction chemotherapy or in previously treated AML patients with relapsed disease has been initiated (NCT03217838). The study is currently enrolling patients in the dose escalation phase."

P1 data • Acute Myelogenous Leukemia • Biosimilar

Biomarker driven phase II umbrella trial study of AZD1775, AZD2014, AZD2811 monotherapy in relapsed small cell lung cancer. (ASCO 2019) - P=N/A, P2; "SUKSES is the first biomarker-driven umbrella study with the largest cohort of genomic profile pre-screened in resistant SCLC patients (n = 275). However, it does not support further development of the current regimens of AZD1775, AZD2811, AZD2014. Altered administration schedule or combination regimen is under development."

Biomarker • Monotherapy • P2 data • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • Thoracic Cancer

Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours. (PubMed, Br J Cancer) - P1 | "At RP2D, AZD2811 was tolerable with G-CSF support. Neutropenia was a pharmacodynamic biomarker."

Journal • Metastases • P1 data • PK/PD data • Dental Disorders • Fatigue • Febrile Neutropenia • Hematological Disorders • Neutropenia • Oncology • Solid Tumor • Stomatitis • AURKB

Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours (Nature, Br J Cancer) - P1 | N=72 | NCT02579226 | Sponsor: AstraZeneca | "We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours....Fifty-one patients received AZD2811. Drug exposure was sustained for several days post-dose. The most common AZD2811-related adverse events (AEs) were fatigue (27.3%) at ≤200 mg/cycle and neutropenia (37.9%) at ≥400 mg/cycle. Five patients had dose-limiting toxicities: grade (G)4 decreased neutrophil count (n = 1, 200 mg; Days 1, 4; 28-day cycle); G4 decreased neutrophil count and G3 stomatitis (n = 1 each, both 400 mg; Day 1; 21-day cycle); G3 febrile neutropenia and G3 fatigue (n = 1 each, both 600 mg; Day 1; 21-day cycle +G-CSF)."

P1 data • Oncology • Solid Tumor

Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours (Nature, Br J Cancer) - P1 | N=72 | NCT02579226 | Sponsor: AstraZeneca | "We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours....Fifty-one patients received AZD2811. Drug exposure was sustained for several days post-dose. The most common AZD2811-related adverse events (AEs) were fatigue (27.3%) at ≤200 mg/cycle and neutropenia (37.9%) at ≥400 mg/cycle. Five patients had dose-limiting toxicities: grade (G)4 decreased neutrophil count (n = 1, 200 mg; Days 1, 4; 28-day cycle); G4 decreased neutrophil count and G3 stomatitis (n = 1 each, both 400 mg; Day 1; 21-day cycle); G3 febrile neutropenia and G3 fatigue (n = 1 each, both 600 mg; Day 1; 21-day cycle +G-CSF)."

P1 data • Oncology • Solid Tumor

Selecting Counterions to Improve Ionized Hydrophilic Drug Encapsulation in Polymeric Nanoparticles. (PubMed, Mol Pharm) - "Solubility data indicated that the pamoic acid/AZD2811 complex has a lower organic phase solubility than AZD2811-free base; hence, it may be expected to precipitate more rapidly in the nanodroplets, thus increasing drug loading. Our work provides a generalizable preformulation framework, complementing traditional performance-indicating parameters, to identify optimal counterions rapidly and accelerate the development of hydrophilic drug PNP formulations while achieving high drug loading without laborious trial-and-error experimentation."

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