BAY-1816032 / Bayer - LARVOL DELTA

BUB1-Mediated G2/M Checkpoint Control and Mitotic Integrity: A Targetable Vulnerability in MPM (EACR 2025) - "Here, we demonstrate the role of BUB1 as an emerging cancer-essential gene and a potential druggable vulnerability in MPM.Material and BUB1 was identified as a vulnerability for MPM cells by a whole-genome CRISPR screen and this role was validated by knockout and pharmacological inhibition (BAY-1816032)... Our findings establish BUB1 as a critical regulator of mitosis by modulating the G2/M checkpoint in MPM. The observed mitotic defects and altered transcriptional programs reinforce the role of BUB1 in MPM pathophysiology. These results highlight BUB1 as a key dependency in MPM and provide a strong rationale for targeting BUB1 in preclinical models of MPM therapy."

Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Pleural Mesothelioma • Solid Tumor • BUB1 • CCNA2 • CDC20 • CDKN1A

BUB1 Inhibition Overcomes Radio- and Chemoradiation Resistance in Lung Cancer. (PubMed, Cancers (Basel)) - "Background: Despite advances in targeted therapies and immunotherapies, traditional treatments like microtubule stabilizers (paclitaxel, docetaxel), DNA-intercalating platinum drugs (cisplatin), and radiation therapy remain essential for managing locally advanced and metastatic lung cancer... BUB1 inhibitor (BAY1816032) was combined with cisplatin, paclitaxel, a PARP inhibitor olaparib, and radiation in cell proliferation and radiation-sensitization assays...Furthermore, we present the novel finding that BUB1 inhibition sensitized both NSCLC and SCLC to radiotherapy and chemoradiation. Our results demonstrate BUB1 inhibition as a promising strategy to sensitize lung cancers to radiation and chemoradiation therapies."

IO biomarker • Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • BAX • BCL2 • BUB1 • CASP9 • PCNA • TP53

BUB1 Inhibition Sensitizes TNBC Cell Lines to Chemotherapy and Radiotherapy. (PubMed, Biomolecules) - "In this study, we evaluated the effectiveness of BAY1816032 with a PARP inhibitor (olaparib), platinum agent (cisplatin), and microtubule poison (paclitaxel) alone or in combination with radiotherapy using cytotoxicity and clonogenic survival assays. The data presented here are significant as they provide proof that inhibition of BUB1 kinase activity sensitizes TNBC cell lines to a PARP inhibitor and radiation, irrespective of BRCA1/2 mutation status. Due to the ability of the BUB1 inhibitor to sensitize TNBC to different classes of drugs (platinum, PARPi, microtubule depolarization inhibitors), this work strongly supports the role of BUB1 as a novel molecular target to improve chemoradiation efficacy in TNBC and provides a rationale for the clinical evaluation of BAY1816032 as a chemosensitizer and chemoradiosensitizer in TNBC."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • BRCA1 • BRCA2 • BUB1

Exploring Cancer Dependencies with Genome-Wide CRISPR Screens: Unveiling BUB1 Kinase as a Druggable Vulnerability in Malignant Pleural Mesothelioma (EACR 2024) - "Finally, single cell knock-out clones were obtained for characterization of molecular and cellular changes in BUB1-deficient MPM cells.Results and Discussions BUB1 gene depletion or inhibition by BUB1 kinase inhibitor, BAY-1816032, attenuated proliferation and 3D anchorage-independent growth of MPM cells...Most critically, higher levels of BUB1 expression were associated with shorter MPM patient survival.Conclusion BUB1 is a potent cancer dependency gene and may potentially serve as a biomarker and therapeutic target for MPM treatment. Further studies focusing on molecular interactions and characterization on preclinical models, such as patient-derived tumoroids, will contribute to the understanding of the therapeutic potential of BUB1 in MPM."

Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Solid Tumor • AURKA • BUB1 • VPS37A

BUB1 regulates non-homologous end joining pathway to mediate radioresistance in triple-negative breast cancer. (PubMed, J Exp Clin Cancer Res) - "BUB1 ablation sensitizes TNBC cell lines and xenografts to RT and BUB1 mediated radiosensitization may occur through NHEJ. Together, these results highlight BUB1 as a novel molecular target for radiosensitization in women with TNBC."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BUB1

[PREPRINT] BUB1 inhibition sensitizes lung cancer cell lines to radiotherapy and chemoradiotherapy (bioRxiv) - "BUB1 expression assessed by immunostaining of lung tumor microarrays (TMAs) confirmed higher BUB1 expression in NSCLC and SCLC compared to that of normal tissues. BUB1 overexpression in lung cancer tissues correlated directly with expression of TP53 mutations in non-small cell lung cancer (NSCLC). Elevated BUB1 levels correlated with poorer overall survival in NSCLC and small cell lung cancer (SCLC) patients. A BUB1 inhibitor (BAY1816032) synergistically sensitized lung cancer cell lines to paclitaxel and olaparib. Additionally, BAY1816032 enhanced cell killing by radiation in both NSCLC and SCLC. Molecular changes following BUB1 inhibition suggest a shift towards pro-apoptotic and anti-proliferative states, indicated by altered expression of BAX, BCL2, PCNA, and Caspases 9 and 3."

Preclinical • Preprint • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

BUB1 interferes with the repair of radiation-induced DNA damage to radiosensitize triple-negative breast cancer (AACR 2024) - "In multiple TNBC cell lines, cell proliferation assays revealed that pharmacological (BAY1816032) or genomic (CRISPR) ablation of BUB1 was cytotoxic...Our findings demonstrate that ablation of BUB1 sensitizes TNBC cell lines and xenograft to RT and BUB1 mediated radiosensitization may occur through NHEJ. Our results suggest that BUB1 may serve as a novel molecular target for radiosensitization in women with TNBC."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BUB1

Enhancing lung cancer sensitivity to chemotherapy, radiation, and chemo-radiation through inhibition of a mitotic checkpoint kinase BUB1 (AACR 2024) - "In vitro experiments used four NSCLC and two SCLC cell lines with BUB1 inhibitor (BAY1816032), Paclitaxel, Cisplatin and Olaparib. Among SCLC cell lines, NCI-H1876 demonstrated higher radiosensitivity upon BUB1 ablation compared to NCI-H2198, potentially due to genetic differences/mutations affecting radiation response. The study highlights the potential of BUB1i in enhancing the sensitivity of NSCLC and SCLC cells to radiotherapy and chemotherapy and provide rationale to explore BUB1i as a novel approach to enhance lung cancer therapy in clinical trials."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor • BUB1 • TP53

BUB1/KIF14 complex promotes anaplastic thyroid carcinoma progression by inducing chromosome instability. (PubMed, J Cell Mol Med) - "Inhibition of BUB1 by its inhibitor BAY-1816032 also exhibited considerable anti-tumour activity...Overexpression of the KIF14ΔSer1292 mutant was unable to facilitate the aggressiveness of ATC cells when compared with that of the wild type. Collectively, these findings demonstrate that the BUB1/KIF14 complex drives the aggressiveness of ATC by inducing CIN."

Journal • Endocrine Cancer • Oncology • Solid Tumor • Thyroid Gland Anaplastic Carcinoma • Thyroid Gland Carcinoma • Thyroid Gland Papillary Carcinoma • BUB1 • KIF14

Bub1 suppresses inflammatory arthritis-associated bone loss in mice through inhibition of TNFα-mediated osteoclastogenesis. (PubMed, J Bone Miner Res) - "Finally, osteoclastogenesis was increased by Bub1 inhibitor BAY1816032 treatment in BMMs derived from wildtype mice. These data suggest that Bub1 expressed in macrophages plays a protective role against inflammatory arthritis-associated bone loss through inhibition of inflammation-mediated osteoclastogenesis."

Journal • Preclinical • Immunology • Inflammation • Inflammatory Arthritis • Musculoskeletal Diseases • Orthopedics • Osteoporosis • Rheumatoid Arthritis • Rheumatology • BUB1 • IL1B • ITGAM • PTPRC • TNFA

The mitotic checkpoint kinase BUB1 is a direct and actionable target of MYB in adenoid cystic carcinoma. (PubMed, FEBS Lett) - "Molecular profiling confirmed that MYB-driven gene expression causes a transition into an ACC-like state. Using this new cell model, we identified BUB1 as a targetable kinase directly controlled by MYB, whose pharmacological inhibition caused MYB-dependent synthetic lethality, growth arrest and apoptosis of patient-derived cells and organoids."

Journal • Adenoid Cystic Carcinoma • Head and Neck Cancer • Oncology • Solid Tumor • BUB1

Ablation of mitotic checkpoint kinase BUB1 sensitizes lung adenocarcinoma to different classes of chemotherapy, radiation, and chemo-radiation (AACR 2023) - "MTT cell proliferation and clonogenic cell survival studies were conducted with pharmacological (BAY1816032) and genomic (CRISPR) BUB1 ablation in combination with Platinum (Cisplatin), Taxol (Paclitaxel) or a PARP inhibitor (Olaparib) without/with radiation. Detailed mechanistic studies combining BUB1 ablation with chemo-radiation are underway to delineate signaling cascades involved in BUB1 driven chemo-radiation sensitization. Our data provides evidence that BUB1 inhibition sensitizes lung adenocarcinoma to radiotherapy, different classes of chemotherapy and chemo-radiation through DNA-double strand break repair pathways and provides rationale for clinical trials that combine BUB1 inhibition with chemo-radiation in NSCLC."

Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • BUB1

BUB1 inhibition radiosensitizes triple-negative breast cancer by targeting the DNA-damage repair pathways (AACR 2023) - "MTT assay in several TNBC cell lines demonstrated that pharmacological (BAY1816032) or genomic (CRISPR) ablation of BUB1 was cytotoxic...Our findings demonstrate that both genetic and pharmacological inhibition of BUB1 sensitizes TNBC cells to RT and that BUB1 mediated radiosensitization may occur through NHEJ pathway. Our results suggest that BUB1 may represent a novel molecular target for radiosensitization in women with TNBC."

Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BUB1

Inhibition of BUB1 suppresses tumorigenesis of osteosarcoma via blocking of PI3K/Akt and ERK pathways. (PubMed, J Cell Mol Med) - "Inhibition of BUB1 markedly suppressed cell proliferation and tumour growth, cell migration, invasion and induced cell apoptosis of OS by blocking the PI3K/Akt and ERK signalling pathways. Thus, our study suggested that overexpression of BUB1 protein contributed to poor survival of OS patients and that inhibition of BUB1 resulted in considerable anti-tumour activity associated with proliferation, migration, invasion and apoptosis of OS."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Inhibition of BUB1 Kinase by BAY 1816032 Sensitizes Tumor Cells towards Taxanes, ATR and PARP Inhibitors in vitro and in vivo. (PubMed, Clin Cancer Res) - "Our findings suggest clinical proof of concept studies evaluating BAY 1816032 in combination with taxanes or PARP inhibitors in order to enhance their efficacy and potentially overcome resistance."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer