ispinesib (SB-715992) / Cytokinetics - LARVOL DELTA

Role of kinesin and Bcl-2 protein association in prostate cancer therapeutic resistance to taxane chemotherapy (AACR 2025) - "This study aims to understand the contribution of Bcl-2 and kinesin protein interactions and their co-targeting by cabazitaxel (2nd line taxane chemotherapy) and kinesin inhibitor ispinesib, to overcome therapeutic resistance in prostate cancer. Two prostate cancer cell lines were used, the LNCaP-Bcl-2 and the C4-2BDR. These studies suggest a functional Bcl-2 association with mitotic spindle protein, kinesin and proteins involved in cytoskeleton organization and remodeling, that might result in resistance to taxane chemotherapy. These findings are of therapeutic significance in identifying a potential targeting value of Bcl-2 association with HSET to increase the therapeutic vulnerability in advanced prostate tumors."

IO biomarker • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • BCL2 • CDH1 • KIFC1 • VIM

Fragment-Based Drug Discovery of KIF11 Inhibitors for Glioblastoma Treatment: Molecular Insights and Therapeutic Potential. (PubMed, Drug Res (Stuttg)) - "Existing drugs, such as ispinesib, are limited by side effects and multidrug resistance...Our findings identified Mol-121026 as a top candidate with a docking score of -10.2 kcal/mol and MM/GBSA binding energy of -19.10 kcal/mol. Molecular dynamics simulations revealed stable interactions with key residues GLU116 and GLU118, supporting its potential as a promising KIF11 inhibitor."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • KIF11

A High-Throughput Immune-Oncology Screen Identifies Immunostimulatory Properties of Cytotoxic Chemotherapy Agents in TNBC. (PubMed, Cancers (Basel)) - " Four chemotherapy agents were chosen as priority hits for mechanistic follow-up due to their ability to enhance T-cell-mediated cytotoxicity at multiple doses and multiple time points: paclitaxel, bleomycin sulfate, ispinesib, and etoposide. Based on the ability to increase tumor cell susceptibility to T-cell-mediated cytotoxicity while minimizing T-cell toxicity, bleomycin was identified as the most promising lead candidate. Overall, the results of these studies provide mechanistic insight into potential new chemotherapy partners to enhance anti-PD-1 efficacy in TNBC patients."

IO biomarker • Journal • Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • HER-2 • HMGB1 • PD-L1

Resistance to spindle inhibitors in glioblastoma depends on STAT3 and therapy induced senescence. (PubMed, iScience) - "Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of activated STAT3. Targeting STAT3 restores sensitivity to each of these drugs by depleting the senescent subpopulation and inducing quiescent cells to enter the mitotic cycle. These results support a therapeutic strategy of targeting STAT3-dependent therapy-induced senescence to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • STAT3 • TGFB1

Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer: A Plausible Alliance to Enhance Cell Death. (PubMed, Cancers (Basel)) - " We analyzed the effects of co-treating OSCC cells with small molecules targeting MPS-1 (BAY1217389), Aurora-B (Barasertib), or KSP (Ispinesib), alongside Cetuximab. Additionally, we examined EGFR, MPS-1, Aurora-B, and KSP expression in OSCC patient samples, revealing their clinicopathologic significance. This combinatorial approach suggests a promising strategy to improve treatment outcomes in OSCC."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • EGFR

Nutritionally physiological cell culture medium and 3D culture influence breast tumour proteomics and anti-cancer drug effectiveness. (PubMed, Pharmacol Res) - "The number of differentially expressed proteins in the different media was greater in 2D than 3D. We conclude that the risk of qualifying inactive compounds in preclinical assessment may be mitigated using additional models incorporating physiological media and 3-dimensionality."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor

Assessment of SWI/SNF chromatin remodeling complex related genes as potential biomarkers and therapeutic targets in pan-cancer. (PubMed, Mol Cancer) - "Aberrant expression of eleven prognostic genes identified from the KIRC prognostic signature and the cytotoxicity of FK866 and Ispinesib mesylate to KIRC were verified by qRT-PCR and CCK-8 assay, respectively. Our study identified SCRGs as potential biomarker and therapeutic targets, providing new insights into SCRC for tumor-targeted therapy."

Biomarker • IO biomarker • Journal • Pan tumor • Clear Cell Renal Cell Carcinoma • Oncology • Renal Cell Carcinoma • Solid Tumor

Deciphering breast cancer prognosis: a novel machine learning-driven model for vascular mimicry signature prediction. (PubMed, Front Immunol) - "Notably, the model unveiled varying therapeutic responses; low-risk patients might achieve greater benefits from immunotherapy, whereas high-risk patients demonstrated a particular sensitivity to certain chemotherapies, such as ispinesib. This model marks a significant step forward in the precise evaluation of breast cancer prognosis and therapeutic responses across different patient groups. It heralds the possibility of refining patient outcomes through tailored treatment strategies, accentuating the potential of machine learning in revolutionizing cancer prognosis and management."

Biomarker • IO biomarker • Journal • Machine learning • Breast Cancer • Oncology • Solid Tumor

Coupling Kinesin Spindle Protein and Aurora B Inhibition with Apoptosis Induction Enhances Oral Cancer Cell Killing. (PubMed, Cancers (Basel)) - "Here, we investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic Navitoclax in oral cancer cells treated with the selective KSP inhibitor, Ispinesib, or AurB inhibitor, Barasertib, aiming to potentiate cell death. A mechanistic analysis underlying this synergistic activity, undertaken by live-cell imaging, is presented. Our data underscore the importance of combining BH3-mimetics with antimitotics in clinical trials to maximize their effectiveness."

Journal • Head and Neck Cancer • Oncology • Oral Cancer • Solid Tumor • AURKB

Resistance to Spindle Inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence. (PubMed, bioRxiv) - "Treating glioblastomas with the spindle inhibitors ispinesib, alisertib, or volasertib creates a subpopulation of therapy induced senescent cells that resist these drugs by relying upon the anti-apoptotic and metabolic effects of activated STAT3. These results support a therapeutic strategy of targeting STAT3-dependent therapy-induced senescence to enhance the efficacy of spindle inhibitors for the treatment of glioblastoma. • Resistance to non-microtubule spindle inhibitors limits their efficacy in glioblastoma and depends on STAT3.• Resistance goes hand in hand with development of therapy induced senescence (TIS).• Spindle inhibitor resistant glioblastomas consist of three cell subpopulations-proliferative, quiescent, and TIS-with proliferative cells sensitive and quiescent and TIS cells resistant.• TIS cells secrete TGFβ, which induces proliferative cells to become quiescent, thereby expanding the population of resistant cells in a spindle inhibitor resistant..."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • STAT3 • TGFB1

Enhancing breast cancer outcomes with machine learning-driven glutamine metabolic reprogramming signature. (PubMed, Front Immunol) - "Intriguingly, the model indicates a differential therapeutic response: low-risk patients may benefit more from immunotherapy, whereas high-risk patients showed sensitivity to specific chemotherapies like BI-2536 and ispinesib. The GMR-model marks a significant leap forward in breast cancer prognosis and the personalization of treatment strategies, offering vital insights for the effective management of diverse breast cancer patient populations."

Biomarker • IO biomarker • Journal • Machine learning • Breast Cancer • Oncology • Solid Tumor

Development of Half-Sandwich Ru, Os, Rh, and Ir Complexes Bearing the Pyridine-2-ylmethanimine Bidentate Ligand Derived from 7-Chloroquinazolin-4(3H)-one with Enhanced Antiproliferative Activity. (PubMed, ACS Omega) - "Herein, we report the synthesis of ispinesib-core pyridine derivative conjugates, which are potent KSP inhibitors, with half-sandwich complexes of ruthenium, osmium, rhodium, and iridium...All studied conjugates increased the percentage of cells in the G2/M phase, simultaneously decreasing the number of cells in the G1/G0 phase, suggesting mitotic arrest. Additionally, ruthenium derivatives were able to generate reactive oxygen species (ROS); however, no significant influence of the organometallic moiety on KSP inhibition was observed, which suggests that conjugation of a KSP inhibitor with the organometallic moiety modulates its mechanism of action."

Journal • Oncology

Multiplexed single-cell lineage tracing of mitotic kinesin inhibitor resistance in glioblastoma. (PubMed, Cell Rep) - "Moreover, treatment of human ex vivo GBM slices with ispinesib demonstrates phenotypic alignment with in vitro responses, underscoring the clinical relevance of our findings. Finally, using retrospective lineage tracing, we identify drugs that are synergistic with ispinesib."

Journal • Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • KIF11

Kinesin Facilitates Phenotypic Targeting of Therapeutic Resistance in Advanced Prostate Cancer. (PubMed, Mol Cancer Res) - "Combinational targeting of kinesins (ispinesib) with cabazitaxel was more effective than single monotherapies in inducing cell death in resistant prostate tumors. Implications: Our findings are of translational significance in identifying kinesin as a novel target of cross-resistance, towards enhancing therapeutic vulnerability and improved clinical outcomes in patients with advanced prostate cancer."

Journal • Metastases • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Metastatic Castration-Resistant Prostate Cancer • Oncology • Prostate Cancer • Solid Tumor • CDH1 • KIFC1 • SLCO1B3 • VIM

Integrating PANoptosis insights to enhance breast cancer prognosis and therapeutic decision-making. (PubMed, Front Immunol) - "Additionally, the model suggested that low-risk patients benefit more from immunotherapy, while high-risk patients are sensitive to specific chemotherapies like BI-2536 and ispinesib. The Panoptosis-model represents a major advancement in breast cancer prognosis and treatment personalization, offering significant insights for effectively managing a wide range of breast cancer patients."

IO biomarker • Journal • Breast Cancer • Oncology • Solid Tumor

Design, synthesis, molecular docking, and in vitro studies of 2-mercaptoquinazolin-4(3H)-ones as potential anti-breast cancer agents. (PubMed, Saudi Pharm J) - "This study investigated the potential anticancer activity of some novel quinazolinone derivatives that were designed on the structural framework of two approved anticancer drugs, Ispinesib (KSP inhibitor) and Idelalisib (PI3Kδ inhibitor), to find out solutions for TNBC. The relative gene expression of pro-apoptotic and anti-apoptotic genes revealed an overexpression of the P53 and BAX genes and a downregulation of the BCL-2 gene by real-time PCR. So, this work proved that compounds 3a, 3b, and 3e could be developed as anticancer candidates, via their P53-dependent apoptotic activity."

IO biomarker • Journal • Preclinical • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ANXA5 • BAX • BCL2 • ER • HER-2 • PGR • PIK3CD • TP53

Requirement of microtubules for secretion of a micronemal protein CpTSP4 in the invasive stage of the apicomplexan Cryptosporidium parvum. (PubMed, mBio) - "The secretion and microtubular distribution could be completely blocked by the selective kinesin-5 inhibitors SB-743921 and SB-715992, resulting in the accumulation of CpTSP4 in micronemes...Additionally, a novel heparin-binding motif is identified and biochemically validated, which contributes to the nanomolar binding affinity of CpTSP4 to host cells. These findings indicate that kinesin-dependent microtubular trafficking is critical to CpTSP4 secretion, and heparin/heparan sulfate is one of the ligands for this micronemal protein."

Journal • Infectious Disease

Cancer-Associated Fibroblasts Together with a Decline in CD8+ T Cells Predict a Worse Prognosis for Breast Cancer Patients. (PubMed, Ann Surg Oncol) - "This study highlighted the significance of CAFs in breast cancer biology and provided compelling evidence of their impact on patient outcomes and treatment response. The findings offer valuable insights into the potential of CAFs as prognostic and predictive biomarkers and support the development of CAF-targeted therapies to improve breast cancer management."

Journal • Breast Cancer • Immune Modulation • Immunology • Oncology • Solid Tumor • CAFs • CD8

Selectivity and Safety of VIP943: A Novel CD123-Targeting Antibody-Drug Conjugate (ADC) Using a Proprietary Linker and Payload Class (ASH 2023) - "The freshly prepared mixture was then incubated VIP716 and ispinesib, a clinical stage KSPi. Additionally, toxicology in non-human primates and in vivo TK studies confirm safety, favorable drug exposures, and little non-specific release of the payload. Based on these data, evaluation of VIP943 in human clinical trials is warranted."

Clinical • Acute Myelogenous Leukemia • Anemia • CNS Disorders • Hematological Disorders • Hematological Malignancies • Neutropenia • Oncology • Thrombocytopenia • CD123 • IL3RA • KIF11

Resistance to Targeted Anti-Mitotics in Glioblastoma is Driven by STAT3 Activation and Therapy Induced Senescence (SNO 2023) - "We reported (Kenchappa et al., Cell Reports, 2022) that resistance to one of these—ispinesib, a highly specific inhibitor of the mitotic kinesin Kif11—requires two functions of STAT3: activation of transcription in the nucleus and of oxidative phosphorylation in the mitochondria...We now report that resistance to two other targeted anti-mitotics—alisertib (Aurora Kinase inhibitor) and volasertib (Polo Like Kinase inhibitor)—works similarly and can likewise be reversed with STAT3 inhibitors...We propose that: 1) TIS cells require STAT3 for survival, and that they in turn maintain a drug resistant state by suppressing mitosis in the remaining, non senescent cells through components of the SASP; and 2) by killing TIS cells, STAT3 inhibitors restore anti-mitotic sensitivity in the remaining, non-senescent tumor cells. We propose that this STAT3/TIS model of resistance may also apply to how resistance develops to other GBM therapies, and may guide similar translational..."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • KIF11 • STAT3

Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib - impact of the organometallic group on the antimitotic activity. (PubMed, Dalton Trans) - "The most active derivatives were the ispinesib Ru and Rh conjugates which were able to generate reactive oxygen species (ROS), which may at least partially explain their high cytotoxicity. At the same time, the Os and Ir derivatives acted as KSP inhibitors with no effects on ROS generation."

Journal • Oncology

Improving Localized Radiotherapy for Glioblastoma via Small Molecule Inhibition of KIF11. (PubMed, Cancers (Basel)) - "Standard of care includes surgery, radiotherapy, and chemotherapy with the DNA alkylating agent temozolomide (TMZ). Critical for the translation of this approach, we validated that combination therapy with ispinesib and irradiation led to the greatest increase in survival over either monotherapy alone. Our data highlight KIF11 inhibition in combination with radiotherapy as a new combinatorial approach that reduces the overall radioresistance of GBM and which can readily be moved into clinical trials."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • KIF11

Design, Synthesis and Evaluation of Biological Activity of Ferrocene-Ispinesib Hybrids - Impact of a Ferrocenyl Group on the Antiproliferative and KSP Inhibitory Activity. (PubMed, Chemistry) - "In order to investigate the mode of action further, cell cycle analysis and reactive oxygen species formation were investigated. The improved antiproliferative activity of the most active compounds may be assigned to synergic effect of various factors such as KPS inhibitory activity due to ispinesibe-core and ability to generate ROS and induce mitotic arrest."

Journal

Relationship between efficacy of phase I/II drug ispinesib in medulloblastoma, molecular subtypes, and p53-mutant status. (ASCO 2023) - "Preclinically, our results indicate feasibility of ispinesib treatment in MB, specifically aggressive Group 3 MB. Importantly, p53-mutant SHH MB represents a poor molecular-subtype candidate for ispinesib therapy."

Clinical • P1/2 data • Brain Cancer • Medulloblastoma • Oncology • Solid Tumor • ANXA5 • KIF11 • SHH • TP53

The therapeutic and prognostic role of cuproptosis-related genes in triple negative breast cancer. (PubMed, BMC Bioinformatics) - "In conclusion, CRGs may play important roles in TNBC development, and they can impact tumor immune microenvironment and patient survival. The Key-TNBC-CRGs interact mutually and can be influenced by common BC-related mutations. Additionally, we established a 11-gene risk model with a robust performance in prediction of 5-15-year survival. As well, some new drugs are proposed potentially effective in TNBC based on the CRG strategy."

Biomarker • Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ATP7A • ATP7B • LIAS • NLRP3 • PIK3CA