filanesib (ARRY-520) / Pfizer - LARVOL DELTA

Functional screening identifies kinesin spindle protein inhibitor filanesib as a potential treatment option for hepatoblastoma. (PubMed, NPJ Precis Oncol) - "One of these models showed complete growth arrest. Our results suggest that filanesib is a potential candidate for hepatoblastoma treatment and should be investigated in future clinical trials."

Journal • Hepatoblastoma • Hepatology • Oncology • Pediatrics • Solid Tumor

Targeting Eg5 using Arry520 combats gastric cancer by inducing monopolar spindles. (PubMed, Gene) - "Arry520 exhibits efficiently therapeutic effects on gastric cancer in tumour organoid models, cell-derived xenografts and patient-derived xenografts (PDX) in mice. Collectively, our findings provide evidence for the oncogenic properties of the mitotic protein Eg5 and identify Arry520 as a promising strategy to combat gastric cancer."

Journal • CNS Disorders • Gastric Cancer • Oncology • Solid Tumor • KIF11

FDA approved library screen revealed Ewing and clear cell sarcomas have increased sensitivity to filanesib over other cancer types (AACR 2024) - "We are currently addressing the role of KIF11 in regulating the expression levels of the fusion proteins' associated transcriptional coactivators and downstream target genes. By completing these studies, we aim to, i) outline the mechanism underpinning the relationship between KIF11 and the oncogenic fusion proteins in ES and CCS cells, and ii) gain an understanding of why ES and CCS cells are particularly vulnerable to KIF11 inhibition.This work has been supported in part by the Flow Cytometry and the Molecular Genomics Cores at the H. Lee Moffitt Cancer Center & Research Institute, a comprehensive cancer center designated by the National Cancer Institute and funded in part by Moffitt's Cancer Center Support Grant (P30-CA076292)"

Breast Cancer • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • ATF1 • EWSR1 • FLI1 • KIF11

High-throughput drug screening identifies kinesin spindle inhibitor filanesib as a potential drug for hepatoblastoma management (EACR-AACR 2024) - "These included three heat shock protein inhibitors, such as luminespib, as well as a kinesin inhibitor, filanesib. Further investigations are on-going to evaluate why this HB subtype demonstrated high sensitivity to filanesib and to further characterize the effect of filanesib on HB models. As a conclusion, our approach may open new revenues for personalized therapies in HB treatment."

Gastrointestinal Cancer • Hepatoblastoma • Hepatology • Oncology • Pediatrics • Solid Tumor • CASP3 • CASP7

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

Drug resistance dependent on allostery: A P-loop rigor Eg5 mutant exhibits resistance to allosteric inhibition by STLC. (PubMed, Front Oncol) - "Eg5(T107N) expression was associated also with resistance to the clinical relevant loop-L5 Eg5 inhibitors, Arry-520 and ispinesib. 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."

Journal • CNS Disorders • Oncology

Filanesib plus bortezomib and dexamethasone in relapsed/refractory t(11;14) and 1q21 gain multiple myeloma. (PubMed, Cancer Med) - "Patients with t(11;14) also had an encouraging PFS of 15.0 months. The combination of filanesib, bortezomib, and dexamethasone continues to show safety and encouraging activity in relapsed/refractory multiple myeloma, particularly in those patients with 1q21 gain and t(11;14)."

Clinical • Journal • Hematological Disorders • Hematological Malignancies • Hypertension • Multiple Myeloma • Neutropenia • Oncology • MCL1

The therapeutic effect of KSP inhibitors in preclinical models of cholangiocarcinoma. (PubMed, Cell Death Dis) - "Treatment with KSP inhibitors SB743921 and ARRY520 caused significant tumor suppression in CCA xenograft models in vivo...Moreover, our clinical data as well as the TCGA database showed KIF11 expression was abundant in most CCA tumor specimens and associated with poor outcomes of CCA patients. Our results demonstrate that the therapeutic regimen of KSP inhibitors could be a promising treatment strategy in CCA."

Journal • Preclinical • Biliary Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • KIF11

The therapeutic effect of KSP inhibitors in preclinical models of cholangiocarcinoma (Cell Death Dis) - "Treatment with KSP inhibitors SB743921 and ARRY520 caused significant tumor suppression in CCA xenograft models in vivo. Mechanistically, KSP inhibitors led to the formation of abnormal monopolar spindles, which further resulted in the mitotic arrest and cell death of CCA cells both in vivo and in vitro."

Preclinical • Biliary Cancer • Biliary Tract Cancer • Cholangiocarcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor

Effective Synthesis and Biological Evaluation of Natural and Designed Bis(indolyl)methanes via Taurine-Catalyzed Green Approach. (PubMed, ACS Omega) - "Nevertheless, detailed analysis of the binding poses indicates that BIM derivatives bind the allosteric pocket of the Eg5 motor domain more robustly than Arry520; moreover, unlike Arry520, BIM binding is found to be resistant to drug-resistant mutations of Eg5. Accordingly, a structure-guided mechanism of Eg5 inhibition by synthesized BIM derivatives is proposed."

Journal • Oncology

Targeted treatment options for childhood hepatoblastoma using high-throughput drug screening (ESMO-TAT 2022) - "These were onalespib (a heat shock protein inhibitor (HSPI)), fimepinostat (PI3K/HDAC inhibitor), idasanutlin (MDM2-antagonist), cabazitaxel (microtubule inhibitor), filanesib (kinesin inhibitor), BIIB021 (HSPI), eribulin (microtubule inhibitor), and luminespib (HSPI). The screen revealed many new promising compounds for HB treatment. The efficacy of these agents should be confirmed in in vivo models in the future."

Clinical • Gastrointestinal Cancer • Hepatoblastoma • Oncology • Solid Tumor • MDM2

Kinesin spindle protein inhibitors in cancer: from high throughput screening to novel therapeutic strategies. (PubMed, Future Sci OA) - "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."

Journal • Review • Oncology

Role of KSP inhibitors as anti-cancer therapeutics: an update. (PubMed, Anticancer Agents Med Chem) - "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."

Journal • Allergy • Oncology • Pain

Clinical Efficacy of Intracellular Molecular Inhibitors for Relapsed, Refractory Multiple Myeloma: A Systematic Review of Early Clinical Data (ASH 2018) - "...Forty-eight patients were quad-refractory (refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide) while 31 patients were penta-refractory (including isatuximab/daratumumab)...The best response was seen when selinexor was used in combination with bortezomib (V) and dexamethasone (d) i.e. 77%...The best response was seen when vorinostat was used in combination with V, doxorubicin (DX) and d i.e. 67%...Conclusion : In RRMM patients, vorinostat and selinexor when used in combination regimens demonstrated a weak efficacy with a pooled ORR of 43% and 36% respectively...The data on other intracellular molecular inhibitors (ricolinostat, oprozomib, marizomib, filanesib, dinaciclib, and palbociclib) when used either as single agents or in combination regimens, suggested a poor efficacy with an ORR of < 35%. However, future randomized well designed prospective clinical trials involving a larger population are required to further explore the efficacy of these..."

Clinical • Review • Biosimilar • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

KIF11 inhibitors filanesib and ispinesib inhibit meningioma growth in vitro and in vivo. (PubMed, Cancer Lett) - "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."

Journal • Preclinical • Meningioma • Oncology • Solid Tumor • Transplantation

Eg5 Targeting Agents : From new anti-mitotic based inhibitor discovery to cancer therapy and resistance. (PubMed, Biochem Pharmacol) - "However, one Eg5 inhibitor, Arry-520 (clinical name filanesib), has demonstrated clinical efficacy in patients with multiple myeloma and is scheduled to enter phase III clinical trials. At the same time, new trends in Eg5 inhibitor research are emerging, including an increased interest in novel inhibitor binding sites and a focus on drug synergy with established antitumor agents to improve chemotherapeutic efficacy. This review presents an updated view of the structure and function of Eg5-inhibitor complexes, traces the possible development of resistance to Eg5 inhibitors and their potential therapeutic applications, and surveys the current challenges and future directions of this active field in drug discovery."

Journal • Review • CNS Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

A phase 1 study of filanesib, carfilzomib, and dexamethasone in patients with relapsed and/or refractory multiple myeloma. (PubMed, Blood Cancer J) - No abstract available

Clinical • Journal • P1 data • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

Rethinking Risk-Benefit Assessment for Phase I Multiple Myeloma Trials (ASH 2016) - "Daratumuab, ixazomib, pomalidomide, Isatuximab, marizomib, oprozomib, filanesib, dinaciclib, venetoclax and LGH-447, had single agent anti-myeloma activity and proceeded to later phase clinical trials (Fig. Four new therapeutic agents, panobinostat, daratumumab, elotuzumab, and ixazomib were approved in 2015 matching the record of seven new-agents and 16 regulatory approvals during the past 12 years."

Adverse events • Combination therapy • Biosimilar • Hematological Malignancies • Multiple Myeloma • Oncology

A Phase 2 Trial of Filanesib in Relapsed/Refractory Multiple Myeloma (AfFIRM) (clinicaltrials.gov) - P2; N=160; Not yet recruiting; Sponsor: Array BioPharma

New P2 trial • Biosimilar • Hematological Malignancies • Multiple Myeloma • Oncology

Therapeutic targeting of KSP in preclinical models of high-risk neuroblastoma. (PubMed, Sci Transl Med) - "ARRY-520, an inhibitor of kinesin spindle protein (KSP), was among those causing reduced viability...Furthermore, treatment of mice harboring orthotopic neuroblastoma PDX tumors resulted in increased survival. Our results suggested that KSP inhibition could be a promising treatment strategy in children with high-risk neuroblastoma."

Journal • Preclinical • Neuroblastoma • Oncology • Solid Tumor • MYCN

Filanesib in combination with pomalidomide and dexamethasone in refractory MM patients: safety and efficacy, and association with alpha 1-acid glycoprotein (AAG) levels. Phase Ib/II Pomdefil clinical trial conducted by the Spanish MM group. (PubMed, Br J Haematol) - P1/2 | "Forty-seven RRMM patients with a median of three prior lines (2-8) and 94% refractory to lenalidomide were included: 14 in phase I and 33 in phase II. Most importantly, high levels of AAG can identify patients unlikely to respond to this strategy. Trial registration: clinicaltrials.gov identifier: NCT02384083."

Clinical • Combination therapy • Journal • P1/2 data • Hematological Malignancies • Multiple Myeloma • Oncology

Filanesib (ARRY-520) in Combination With Pomalidomide and Dexamethasone for Relapsed/Refractory (R/R) Multiple Myeloma (MM) Patients (clinicaltrials.gov) - P1/2; N=47; Completed; Sponsor: PETHEMA Foundation; Active, not recruiting ➔ Completed; Trial completion date: Dec 2019 ➔ Mar 2020

Clinical • Combination therapy • Trial completion • Trial completion date • Hematological Disorders • Hematological Malignancies • Multiple Myeloma • Oncology

Is the fate of clinical candidate Arry-520 already sealed? Predicting resistance in Eg5-inhibitor complexes. (PubMed, Mol Cancer Ther) - "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."

Clinical • Journal • Hematological Malignancies • Multiple Myeloma • Oncology

KIF11 and KIF15 mitotic kinesins are potential therapeutic vulnerabilities for malignant peripheral nerve sheath tumors. (PubMed, Neurooncol Adv) - "KIF15 and KIF23 were required for the survival of MPNST cell lines, which were also more sensitive than benign control fibroblasts to the KIF11 inhibitors ispinesib and ARRY-520. 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."

Journal • Genetic Disorders • Neurofibromatosis • Oncology • Solid Tumor

Cytotoxic efficacy of filanesib and melphalan combination is governed by sequence of treatment in human myeloma cells. (PubMed) - Blood Cancer J - No abstract available

Journal • Biosimilar • Hematological Malignancies • Multiple Myeloma • Oncology