- |||||||||| ispinesib (SB-715992) / Cytokinetics
Biomarker, Journal, IO biomarker, Machine learning: Deciphering breast cancer prognosis: a novel machine learning-driven model for vascular mimicry signature prediction. (Pubmed Central) - Aug 21, 2024
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.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, alisertib (MLN8237) / Puma, volasertib (NBL-001) / Oncoheroes, Notable Labs
Journal: Resistance to Spindle Inhibitors in Glioblastoma Depends on STAT3 and Therapy Induced Senescence. (Pubmed Central) - Jun 19, 2024
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.
- |||||||||| BI2536 / Boehringer Ingelheim, ispinesib (SB-715992) / Cytokinetics
Biomarker, Journal, IO biomarker, Machine learning: Enhancing breast cancer outcomes with machine learning-driven glutamine metabolic reprogramming signature. (Pubmed Central) - May 17, 2024
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.
- |||||||||| ispinesib (SB-715992) / Cytokinetics
Journal, Metastases: Kinesin Facilitates Phenotypic Targeting of Therapeutic Resistance in Advanced Prostate Cancer. (Pubmed Central) - Apr 22, 2024
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.
- |||||||||| BI2536 / Boehringer Ingelheim, ispinesib (SB-715992) / Cytokinetics
Journal, IO biomarker: Integrating PANoptosis insights to enhance breast cancer prognosis and therapeutic decision-making. (Pubmed Central) - Mar 24, 2024
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.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, Zydelig (idelalisib) / Gilead
Preclinical, Journal, IO biomarker: Design, synthesis, molecular docking, and in vitro studies of 2-mercaptoquinazolin-4(3H)-ones as potential anti-breast cancer agents. (Pubmed Central) - Feb 15, 2024
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.
- |||||||||| ispinesib (SB-715992) / Cytokinetics
Journal: Requirement of microtubules for secretion of a micronemal protein CpTSP4 in the invasive stage of the apicomplexan Cryptosporidium parvum. (Pubmed Central) - Jan 24, 2024
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.
- |||||||||| ispinesib (SB-715992) / Cytokinetics
Journal: Improving Localized Radiotherapy for Glioblastoma via Small Molecule Inhibition of KIF11. (Pubmed Central) - Jun 28, 2023
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.
- |||||||||| tolvaptan / Generic mfg.
Journal: MD simulation-based screening approach identified tolvaptan as a potential inhibitor of Eg5. (Pubmed Central) - Jun 19, 2023
Since tolvaptan is found to have a significant cytotoxic effect on HeLa cells, it can be developed as a prospective anticancer agent either alone or in combination with other antimitotic drugs. Tolvaptan was identified as an inhibitor of Eg5 in a MD simulation-based virtual screening using a combined pharmacophore model.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, filanesib (ARRY-520) / Pfizer
Journal: Drug resistance dependent on allostery: A P-loop rigor Eg5 mutant exhibits resistance to allosteric inhibition by STLC. (Pubmed Central) - Nov 1, 2022
Biochemical assays showed that in contrast to the wild type Eg5-STLC complex, the ATP binding site of the Eg5(T107N) is accessible for nucleotide exchange only when the inhibitor is present. We predict that resistance can be overcome by inhibitors that bind to other than the Eg5 loop-L5 binding site having different chemical scaffolds, and that allostery-dependent resistance to Eg5 inhibitors may also occur in cells and may have positive implications in chemotherapy since once diagnosed may be beneficial following cessation of the chemotherapeutic regimen.
- |||||||||| ispinesib (SB-715992) / Cytokinetics
Journal: Distinct binding interactions trigger opposite conformational modulations on pathogenic and wildtype Huntingtin exon 1 proteins. (Pubmed Central) - Oct 22, 2022
More specifically, stronger hydrogen bonds serve as the specific binding anchors in pathogenic Htt-exon-1, while stronger hydrophobic interactions dominate in the dynamic binding with wildtype Htt-exon-1. Our simulations provide an atomistic mechanism for the ispinesib selective binding on the pathogenic Htt-exon-1, and further shed light on the general mechanisms of small molecule modulation on intrinsically disordered proteins.
- |||||||||| ispinesib (SB-715992) / Cytokinetics
EGFR and SRC-Mediated Activation of STAT3 Drives Resistance to Mitotic Inhibitors in Glioblastoma, and can be Reversed With FDA-Approved Drugs (Ballroom B) - Sep 28, 2022 - Abstract #SNO2022SNO_91;
We have shown that one of these, a potent inhibitor of the mitotic kinesin Kif11 (ispinesib), is highly active against GBM tumor initiating cells and prolongs survival in murine models of this disease...Furthermore, we find that resistance to several other mitotic inhibitors also utilizes this STAT3-driven mechanism and can likewise be reversed with combined EGFR and SRC inhibition. Thus, our work demonstrates how a promising therapeutic approach, which has been disappointing in GBM, can in fact be rendered effective by anticipating and prospectively treating ab initio the mechanism that drives treatment resistance.
- |||||||||| ispinesib (SB-715992) / Cytokinetics
Journal: Activation of STAT3 through combined SRC and EGFR signaling drives resistance to a mitotic kinesin inhibitor in glioblastoma. (Pubmed Central) - Jun 29, 2022
Simultaneously inhibiting SRC and EGFR reverses this resistance, and combined targeting of these two kinases in vivo with clinically available inhibitors is synergistic and significantly prolongs survival in ispinesib-treated GBM-bearing mice. We thus identify a translationally actionable approach to overcoming Kif11 inhibitor resistance that may work to block STAT3-driven resistance against other anti-cancer therapies as well.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, litronesib (KF 89617) / Kyowa Kirin, Eli Lilly, filanesib (ARRY-520) / Pfizer
Journal: Role of KSP inhibitors as anti-cancer therapeutics: an update. (Pubmed Central) - Jun 22, 2022
Drugs such as filanesib, litronesib, ispinesib have entered clinical trials, the most advanced phase explored being Phase II. KSP inhibitors have exhibited promising results; however, continued exploration is greatly required to establish the clinical potential of KSP inhibitors.
- |||||||||| Ibrance (palbociclib) / Pfizer, ispinesib (SB-715992) / Cytokinetics, Lynparza (olaparib) / Merck (MSD), AstraZeneca
Discovery and preclinical characterization of novel small molecule inhibitors of kinesin KIF18A motor protein with potent activity against chromosomally unstable cancers (Section 16) - Mar 9, 2022 - Abstract #AACR2022AACR_2477;
Importantly, KIF18A inhibitors have minimal toxicity on normal dividing somatic cell types in vitro, including proliferating human bone marrow mononuclear cells, distinct from paclitaxel and small molecule inhibitors of essential mitotic kinases and kinesins. In vivo, we demonstrate that administration of KIF18A inhibitors AM-1882 and AM-5308 induce a robust pharmacodynamic response (pH3, mitotic marker) and frank tumor regressions in two TP53 mutant human HGSOC xenograft models (OVCAR-3, OVCAR-8) at well-tolerated doses.Collectively, our preclinical data provides the first example of a therapeutic strategy to selectively target CIN+ cancers through inhibition of KIF18A motor protein.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, litronesib (KF 89617) / Kyowa Kirin, Eli Lilly, filanesib (ARRY-520) / Pfizer
Review, Journal: Kinesin spindle protein inhibitors in cancer: from high throughput screening to novel therapeutic strategies. (Pubmed Central) - Mar 8, 2022
In this review, we track the medicinal chemistry developmental stages of KSP inhibitors. Moreover, we address the challenges that are faced during the development of KSP inhibitor therapy for cancer and future insights for the latest advances in research that are directed to find active KSP inhibitor drugs.
- |||||||||| Cabometyx (cabozantinib tablet) / Takeda, Exelixis, Ipsen
Clinical, Journal: Efficacy and Synergy of Small Molecule Inhibitors Targeting FLT3-ITD Acute Myeloid Leukemia. (Pubmed Central) - Dec 27, 2021
Together, we suggest WS6, ispinesib, ponatinib and cabozantinib as novel options for targeting FLT3-ITD AML. Whether combinatorial tyrosine kinase and kinesin spindle blockade is effective in eradicating neoplastic (stem) cells in FLT3-ITD AML remains to be determined in clinical trials.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, filanesib (ARRY-520) / Pfizer
Preclinical, Journal: KIF11 inhibitors filanesib and ispinesib inhibit meningioma growth in vitro and in vivo. (Pubmed Central) - Sep 17, 2021
Furthermore, both drugs induced minor hematological side effects, which were less pronounced for filanesib. We identified substantial in vitro and in vivo anti-tumor effects of the KIF11 inhibitors filanesib and ispinesib, with filanesib demonstrating better tolerability, suggesting future use of filanesib for the treatment of aggressive meningioma.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, GSK
Journal, Combination therapy: Targeting the Id1-Kif11 Axis in Triple-Negative Breast Cancer Using Combination Therapy. (Pubmed Central) - Jun 16, 2021
Therapeutic targeting of Kif11 to block the Id1-Kif11 axis was carried out using small molecular inhibitor ispinesib...This work opens up exciting new possibilities of targeting Id targets such as Kif11 in the TNBC subtype, which is currently refractory to chemotherapy. Targeting the Id1-Kif11 molecular pathway in the Id1+ CSCs in combination with chemotherapy and small molecular inhibitor results in more effective debulking of TNBC.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, GSK, Zokinvy (lonafarnib) / Eiger
Journal: Speculative assessment, molecular composition, PDOS, topology exploration (ELF, LOL, RDG), ligand-protein interactions, on 5-bromo-3-nitropyridine-2-carbonitrile. (Pubmed Central) - Jun 8, 2021
Molecular Dynamics simulations were done to assess the stability of the complex. 5B3N2C physiochemical parameters were also compared to those of widely viable medications Ispinesib and Lonafarnib.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, GSK
Preclinical, Journal: Enhancing Brain Retention of a KIF11 Inhibitor Significantly Improves its Efficacy in a Mouse Model of Glioblastoma. (Pubmed Central) - Dec 1, 2020
We further find that elacridar-a P-gp and Bcrp inhibitor-improves brain accumulation of ispinesib, resulting in remarkably reduced tumor growth and extended survival in a rodent model of glioblastoma. Such observations show the benefits and feasibility of pairing a potentially ideal treatment with a compound that improves its brain accumulation, and supports use of this strategy in clinical exploration of cell cycle-targeting therapies in brain cancers.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, GSK
[VIRTUAL] Targeting KIF11 to Radiosensitize Glioblastoma () - Oct 24, 2020 - Abstract #SNO2020SNO_985;
We also demonstrated that invasiveness and self-renewal of CSCs could be targeted with ispinesib, a small molecule inhibitor to KIF11...Using a KIF11 inhibitor combined with irradiation increased survival of mice bearing orthotopic glioblastoma. Our results suggest that targeting KIF11 in combination with radiotherapy is a promising technique to overcome the radio-resistance of CSCs, and holds potential to significantly improve treatment outcomes and extend survival of patients with GBM.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, GSK
Journal: Metal-Dependent Cytotoxic and Kinesin Spindle Protein Inhibitory Activity of Ru, Os, Rh, and Ir Half-Sandwich Complexes of Ispinesib-Derived Ligands. (Pubmed Central) - Oct 4, 2020
The organometallics exhibited varying antiproliferative activity in a series of human cancer cell lines, with the complexes featuring the (R)-enantiomer of the ligand being more potent than the (S)-configured counterparts. Notably, the Rh and Ir complexes demonstrated high KSP inhibitory activity, even at 1 nM concentration, which was independent of the chirality of the ligand, whereas the Ru and especially the Os derivatives were much less active.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, GSK
Journal: Multi-functionalised graphene nanoflakes as tumour-targeting theranostic drug-delivery vehicles. (Pubmed Central) - Sep 4, 2020
In this work, GNFs were multi-functionalised with derivatives of (i) a peptide-based Glu-NH-C(O)-NH-Lys ligand that binds prostate-specific membrane antigen (PSMA), (ii) a potent anti-mitotic drug (R)-ispinesib, (iii) the chelate desferrioxamine B (DFO), and (iv) an albumin-binding tag reported to extend pharmacokinetic half-life in vivo...Image analysis indicated that GNFs have low accumulation and retention in background tissue, with rapid renal clearance. In summary, our study shows that GNFs are suitable candidates for use in theranostic drug design.
- |||||||||| JQ-1 / Roche, ispinesib (SB-715992) / Cytokinetics, GSK, filanesib (ARRY-520) / Pfizer
Journal: KIF11 and KIF15 mitotic kinesins are potential therapeutic vulnerabilities for malignant peripheral nerve sheath tumors. (Pubmed Central) - Jul 10, 2020
Co-targeting KIF11 and BRD4 with ARRY-520 and JQ1 reduced MPNST cell viability, synergistically killing a much higher proportion of MPNST cells than control fibroblasts...The mitotic spindle kinesins KIF11 and KIF15 and the cytokinetic kinesin KIF23 play a clear role in maintaining MPNST cell survival and may represent potential therapeutic vulnerabilities. Although further in vivo evidences are still mandatory, we propose a simultaneous suppression of KIF11, KIF15, and BRD4 as a potential therapy for MPNSTs.
- |||||||||| filanesib (ARRY-520) / Pfizer
Clinical, Journal: Is the fate of clinical candidate Arry-520 already sealed? Predicting resistance in Eg5-inhibitor complexes. (Pubmed Central) - Jul 8, 2020
Molecular dynamics simulations suggest that subtle differences in ligand binding and flexibility in both compound and protein may alter allosteric transmission from the loop L5 site that do not necessarily result in reduced inhibitory activity in mutated Eg5 structures. Whilst we predict that cells challenged with Arry-520 in the clinical setting are likely to acquire resistance through point mutations in the Eg5 binding site, the data for ispinesib suggests that this resistance mechanism is not scaffold independent as previously thought, and new inhibitors can be designed that retain inhibitory activity in these resistant cells.
- |||||||||| Journal: A High-Throughput Screen of a Library of Therapeutics Identifies Cytotoxic Substrates of P-glycoprotein. (Pubmed Central) - Mar 4, 2020
We used the CellTiter-Glo viability assay to test library compounds against parental KB-3-1 human cervical adenocarcinoma cells and the colchicine-selected subline KB-8-5-11 that overexpresses P-gp...ABCG2 was also found to confer high levels of resistance to AT9283, GSK-690693, and gedatolisib, whereas ispinesib, AT7519, and KW-2478 were weaker substrates...Of the 10,804 compounds screened, a total of 90 substrates were identified of which 55 were novel. P-gp expression may adversely affect the oral bioavailability or brain penetration of these compounds.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, GSK
Design and synthesis of novel ispinesib prodrugs (Exhibit Hall D, Pennsylvania Convention Center) - Feb 13, 2020 - Abstract #ACSSp2020ACS_Sp_16527;
The rapid degradation of phosphonium derivatives in alkaline pH implies an intracellular release of the parent drug. The stability of phosphoramidates for at least 2h also implies a sufficient in vivo distribution time in order for the prodrug to reach the target.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, GSK
Design and synthesis of novel ispinesib prodrugs (Exhibit Hall A, Pennsylvania Convention Center) - Feb 13, 2020 - Abstract #ACSSp2020ACS_Sp_8998;
The rapid degradation of phosphonium derivatives in alkaline pH implies an intracellular release of the parent drug. The stability of phosphoramidates for at least 2h also implies a sufficient in vivo distribution time in order for the prodrug to reach the target.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, GSK
ENHANCING BRAIN RETENTION OF A KIF11 INHIBITOR SIGNIFICANTLY IMPROVES ITS EFFICACY IN A MOUSE MODEL OF GLIOBLASTOMA () - Nov 12, 2019 - Abstract #SNO2019SNO_1721;
We also show that elacridar—an inhibitor of the P-gp and Brcp efflux transporters—enhances delivery of ispinesib, and that co-administration of ispinesib with elacridar markedly slows tumor proliferation and prolongs survival in a mouse model of this disease. These results demonstrate the feasibility and efficacy of combining a potentially ideal therapeutic with a compound that enhances brain retention of this therapeutic, and provides support for utilizing this approach in clinical investigations of KIF11 inhibitors in GBM.
- |||||||||| ispinesib (SB-715992) / Cytokinetics, GSK
Targeting KIF11 to radiosensitize glioblastoma. (Ballroom Lawn) - Oct 29, 2019 - Abstract #SNO2019SNO_678;
We also demonstrated that invasiveness and self-renewal of CSCs could be targeted with ispinesib, a small molecule inhibitor to KIF11...Using a KIF11 inhibitor combined with irradiation increased survival of mice bearing orthotopic glioblastoma. Our results suggest that targeting KIF11 in combination with radiotherapy is a promising technique to overcome the radio-resistance of CSCs, and holds potential to significantly improve treatment outcomes and extend survival of patients with GBM.
- |||||||||| ispinesib (SB-715992) / Cytokinetics
Enrollment change, Trial termination, Metastases: A Study of Ispinesib in Metastatic Breast Cancer (clinicaltrials.gov) - Apr 30, 2019
P1/2, N=16, Terminated,
Our results suggest that targeting KIF11 in combination with radiotherapy is a promising technique to overcome the radio-resistance of CSCs, and holds potential to significantly improve treatment outcomes and extend survival of patients with GBM. N=100 --> 16 | Completed --> Terminated; Trial stopped for administrative reasons prior to official determination of MTD.
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