empesertib (BAY1161909) / Bayer - LARVOL DELTA

Integrative systems biology and drug repurposing reveal key regulatory hubs and a prognostic signature in gastric cancer. (PubMed, Discov Oncol) - "This comprehensive pipeline identified key molecular drivers, upstream regulators, survival-associated biomarkers, and potential therapeutic compounds in gastric cancer. The findings offer a robust framework for future experimental validation and contribute to the development of personalized therapeutic strategies for improving clinical outcomes in gastric cancer."

Journal • Gastric Cancer • Oncology • Solid Tumor • CDC37 • CTNNB1 • HSP90AB1 • SRSF7

Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling. (PubMed, Neoplasia) - "Here, we extended those studies into syngeneic murine models of TNBC using two TTK inhibitors: empesertib and the novel TTK inhibitor CFI-402257 (also known as luvixasertib) that was recently granted FDA fast track approval in breast cancer. Taken together, these studies demonstrate that TTK inhibition enhances radiosensitivity and TTK inhibition with RT modulates the immune landscape of TNBC. Collectively, this combination may represent a novel therapeutic strategy to improve outcomes for patients with TNBC by both direct tumor cytotoxicity and by promoting an immune-responsive environment."

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

Augmenting Type 1 interferon antitumoral immune signaling in triple-negative breast cancer (TNBC) via combined radiotherapy and monopolar spindle kinase I (Mps1) inhibition (IMMUNOLOGY 2025) - "Mps1 inhibition (via empesertib or CFI-402257) combined with RT inhibited TNBC growth in vitro and in vivo. These data demonstrate that Mps1 inhibition radiosensitizes TNBC models through increased micronuclei formation and induces T1IFN signaling, suggesting that combination therapy might more effectively treat TNBC and potentiate immune responses in women with TNBC. Future work will examine the underlying implications on the antitumoral immune response.Keywords: Animals Human Rodent; Molecules Cytokines MHC; Processes Cell Proliferation"

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CXCL10 • IFNB1

The immune regulation and therapeutic potential of the SMAD gene family in breast cancer. (PubMed, Sci Rep) - "Interestingly, patients with high expression of SMAD3 exhibited significant resistance to dasatinib and staurosporine, while high sensitivity to tamoxifen and auranofin. In addition, SMAD3 knockdown promoted the apoptosis of BT-549 cells and decreased cell activity, and BAY-1161909 and XK-469 increased drug efficacy. In conclusion, genes of the SMAD family play a crucial role in the development of breast cancer."

Journal • Breast Cancer • Oncology • Solid Tumor • SMAD2 • SMAD3 • SMAD4 • SMAD7 • TGFB1

The radiosensitizing effects of monopolar spindle kinase I in syngeneic models of triple negative breast cancer and its implications on the tumor immune microenvironment (P875) (IMMUNOLOGY 2023) - "We hypothesize that the TTK inhibitor empesertib radiosensitizes murine TNBC models to radiation in vitro and in vivo and modulates the immune tumor microenvironment...This combined therapy suggests that changes in the underlying immune mechanisms due to TTK inhibition and radiation are important in TNBC. Future work will examine the mechanisms of TTK inhibition and radiation on systemic and tumoral immune changes."

Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Targeting monopolar spindle kinase I (TTK) as a radiosensitizing strategy in syngeneic murine models of triple negative breast cancer (TNBC) and its implications on the tumor immune microenvironment (AACR 2023) - "Tumor growth was monitored and, following the completion of the study, final tumor weights were recorded and tumor tissue was collected to perform immunofluorescent microscopy. Single-agent TTK inhibition via treatment with the ATP-competitive inhibitor empesertib inhibits the growth of murine TNBC cell lines with IC50 values up to 30nM... Our data suggests that TTK inhibition and radiotherapy is synergistic in murine TNBC and alters the tumor immune microenvironment. This combined therapy suggests that changes in the underlying immune mechanisms as a result of the synergistic treatment efficacy are important in TNBC. Future work will examine the underlying mechanisms of TTK inhibition and radiotherapy on systemic and tumoral immune changes."

Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • TTK

First-in-human study of the monopolar spindle 1 (Mps1) kinase inhibitor BAY 1161909 in combination with paclitaxel in subjects with advanced malignancies (ESMO 2018) - P1; "BAY in combination with Pac demonstrated good tolerability with manageable AEs and preliminary evidence of efficacy. Study with the follow-up compound BAY 1217389 is ongoing."

Clinical • Combination therapy • P1 data • Non Small Cell Lung Cancer • Ovarian Cancer

Treating Cancer by Spindle Assembly Checkpoint Abrogation: Discovery of Two Clinical Candidates, BAY 1161909 and BAY 1217389, Targeting MPS1 Kinase. (PubMed, J Med Chem) - "The imidazopyrazine series displayed more than 10-fold higher potencies; however, in the early project phase, this series suffered from poor metabolic stability. Here, we outline the evolution of the two hit series to clinical candidates BAY 1161909 and BAY 1217389 and reveal how both clinical candidates bind to the ATP site of MPS1 kinase, while addressing different pockets utilizing different binding interactions, along with their synthesis and preclinical characterization in selected in vivo efficacy models."

Clinical • Journal • Oncology • MPS1

Polymer mediated drug supersaturation controlled by drug-polymer interactions persisting in aqueous environment. (PubMed, Mol Pharm) - "We investigated the drug-polymer interactions in nonaqueous and aqueous environments between a poorly water-soluble drug, BAY1161909 (909), and two commonly used polymers in amorphous solid dispersions, i.e., PVP and HPMC-AS...In summary, we concluded that polymer mediated drug supersaturation was controlled by drug-polymer interactions persisting in aqueous environment. Therefore, the physical nature of drug-polymer interaction, as well as the dissolution kinetic of the drug and polymer, are all critically important to achieve an optimal ASD formulation design."

Journal

Discovery of orally available and potent MPS1(TTK) kinase inhibitors for anti-cancer drugs (AACR 2019) - "...Some of MPS1 inhibitors (NMS-P153, BOS-172722, CFI-402257, BAY-1217389, and BAY-1161909) are in clinical trials. These compounds are treated for solid tumors with or without Paclitaxel...The compounds selectively inhibit MPS1 based on kinase profiling and decrease phosphorylation of MPS1 and Phospho-HH3 signaling, effectively. Some of compounds were selected for further preclinical studies."