ABT-751 / AbbVie, Eisai - LARVOL DELTA

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

A high-throughput immune-oncology screen identifies immunostimulatory properties of low dose chemotherapy in triple negative breast cancer (AACR 2024) - "Five 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 timepoints: paclitaxel, bleomycin sulfate, kinesin-inhibitor, ABT-751, and etoposide. We further found that low doses of these agents do not negativity affect CD8+ T-cell proliferation, whereas high doses may have deleterious effects on CD8+ T-cell functioning. The results of these studies provide mechanistic insight into potential new chemotherapy partners to enhance anti-PD-1 efficacy in TNBC patients and suggest benefit to further investigating the immunostimulatory potential of low dose chemotherapy."

IO biomarker • Late-breaking abstract • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CD8 • HER-2

Evaluation of ABT-751, a novel anti-mitotic agent able to overcome multi-drug resistance, in melanoma cells. (PubMed, Cancer Chemother Pharmacol) - "Our study confirms that ABT-751 is active against melanoma cell lines and models of MDR at physiologically relevant concentrations, it inhibits P-gp ATPase activity, and it may be a BCRP and/or MDR3 substrate. ABT-751 warrants further investigation alone or in tandem with other drug efflux transporter inhibitors for hard-to-treat MDR melanoma."

Journal • Lung Cancer • Melanoma • Oncology • Solid Tumor

Mitotic enrichment as an efficient radiosensitization strategy for intracranial tumors (SNO 2023) - "This tubulin inhibitor (ABT-751) efficiently radiosensitizes a range of preclinical tumor models representing adult and pediatric, primary and metastatic brain tumors...We are currently expanding our preclinical development of mitotic enrichment as a radiosensitization strategy to other targets and cancers and have designed a phase 0/I trial for adult GBM to demonstrate induction of mitotic enrichment and tolerability when combined with radiotherapy. We expect to start enrollment in this trial soon."

Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Pediatrics • Solid Tumor

Glioblastoma CD105 cells define a SOX2 cancer stem cell-like subpopulation in the pre-invasive niche. (PubMed, Acta Neuropathol Commun) - "Finally, screening for 88 clinical drugs revealed that GBM CD105 cells are resistant to most chemotherapeutics except Doxorubicin, Idarubicin, Fludarabine and ABT-751. Our study provides a rationale for targeting tumoral CD105 cells in order to reshape the tumor microenvironment and block GBM progression."

Cancer stem cells • Journal • Brain Cancer • Glioblastoma • Glioma • Oncology • Solid Tumor • Transplantation • CCL2 • CXCL1 • CXCL8 • ENG • IL6 • NES • SOX2 • VIM

Synthesis and biological evaluation of N-alkyl sulfonamides derived from polycyclic hydrocarbon scaffolds using a nitrogen-centered radical approach. (PubMed, Org Biomol Chem) - "Results of the viability assays have identified compounds that exhibit higher potency than other known anticancer agents such as indisulam and ABT-751. Additionally, the physicochemical and drug-likeness properties of the synthesized compounds have been determined experimentally and using in silico predictive tools. The initial exploration into sulfonamide insertion into PH cores has resulted in a number of compounds that warrant further development to produce molecules with therapeutic value."

Journal • Infectious Disease • Oncology

Discovery of 4-methoxy-N-(1-naphthyl)benzenesulfonamide derivatives as small molecule dual-target inhibitors of tubulin and signal transducer and activator of transcription 3 (STAT3) based on ABT-751. (PubMed, Bioorg Chem) - "Further experiments showed that DL14 not only competitively bound to colchicine binding site to inhibit tubulin polymerization with IC values 0.83 μM, but also directly bound to STAT3 protein to inhibit STAT3 phosphorylation with IC value of 6.84 μM. In terms of single target inhibition, DL14 is slightly inferior to positive drugs, but it shows a good anti-tumor effect in vivo, and can inhibit >80% of xenograft tumor growth. This study describes a novel 4-methoxy-N-(1-naphthyl) benzenesulfonamide skeleton as an effective double-targeted anticancer agent targeting STAT3 and tubulin."

Journal • Oncology

ABT-751 Induces Multiple Anticancer Effects in Urinary Bladder Urothelial Carcinoma-Derived Cells: Highlighting the Induction of Cytostasis through the Inhibition of SKP2 at Both Transcriptional and Post-Translational Levels. (PubMed, Int J Mol Sci) - "ABT-751 triggered autophagy and apoptosis, downregulated the mechanistic target of rapamycin kinase (MTOR) and upregulated several pro-apoptotic proteins that are involved in extrinsic and intrinsic apoptotic pathways. Our results suggested that ABT-751 may act as an anti-cancer drug by inhibiting cell migration, invasion yet inducing cell cycle arrest, autophagy and apoptosis in distinct UBUC-derived cells. Particularly, the upstream molecular mechanism of its anticancer effects was identified as ABT-751-induced cytostasis through the inhibition of SKP2 at both transcriptional and post-translational levels to stabilize cyclin dependent kinase inhibitor 1A (CDKN1A) and CDKN1B proteins."

Journal • Bladder Cancer • Oncology • Solid Tumor • Urothelial Cancer • CDKN1A • CDKN1B • mTOR • NFKBIA • SKP2

Synthesis and structure-activity relationships of 5-phenyloxazole-2-carboxylic acid derivatives as novel inhibitors of tubulin polymerization. (PubMed, Bioorg Med Chem Lett) - "N,5-diphenyloxazole-2-carboxamides 6, 7, and 9, which mimicked ABT751, showed improved cytotoxicity compared with ABT751. Molecular docking studies indicated that compound 9 bound to the colchicine binding site of tubulin. Our findings provided insights into useful SARs for further structural modification of inhibitors of tubulin polymerization."

Journal • Oncology

Discovery of novel 2-aryl-3-sulfonamido-pyridines (HoAns) as microtubule polymerization inhibitors with potent antitumor activities. (PubMed, Eur J Med Chem) - "Drugs targeting taxol or vinca binding site of tubulin have been proved an effective way to against cancer...Mechanism studies indicated that compound HoAn32 bound to the colchicine site of β-tubulin, resulting in colony formation inhibition, G2/M phase cell cycle arrest, cell apoptosis as well as increased the generation of ROS in both RKO and SW620 cells...Furthermore, compound HoAn32 also exhibited outstanding antitumor activity in SW620 xenograft tumor models without observable toxic effects, which was more potent than that of ABT-751. In conclusion, our findings suggest that compound HoAn32 may be a promising microtubule destabilizing agent and deserves for further development in cancer therapy."

Journal • Oncology

Inhibition of the formation of autophagosome but not autolysosome augments ABT-751-induced apoptosis in TP53-deficient Hep-3B cells. (PubMed, J Cell Physiol) - "ABT-751 also induced autophagy soon after the occurrence of apoptosis through the suppression of AKT serine/threonine kinase/mechanistic target of rapamycin signaling pathway. Pharmacological inhibition of autophagosome (early autophagy) but not autolysosome (late autophagy) enhanced ABT-751-induced apoptosis in TP53-deficient Hep-3B cells. Our study provided a new strategy to augment ABT-751-induced apoptosis in TP53-deficient cells."

Journal • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor

Conformational states of E7010 is complemented by micro-clusters of water inside the α,β-Tubulin core. (PubMed, J Chem Inf Model) - "At the same time the two other binding modes are elucidated to be quasi degenerate with the native state and that indicates the further possibility in gaining more entropic stabilization of the complex. The role of such 'bridging' water clusters to enhance the protein-ligand interaction will be insightful for designing next generation prospective compounds in the field of cancer therapeutics."

Journal • Oncology

Design, synthesis, and evaluation of N-phenyl-4-(2-phenylsulfonamido)-benzamides as microtubule-targeting agents in drug-resistant cancer cells, displaying HDAC inhibitory response. (PubMed, Eur J Med Chem) - "A new compound (16c) displays promising anticancer activity with GI of 22 ± 2 and 12 ± 0.1 nM in vincristine-resistant nasopharyngeal (KB-Vin) cancer cells and etoposide-resistant nasopharyngeal (KB-7D) cancer cells and is better than vincristine, etoposide, ABT-751, and MS-275. Compound 16c also displays inhibitory activity against HDAC 1 and HDAC 2 with IC values of 1.07 μM, and 1.47 μM, respectively. These findings may lead to a new type of structural motif for future development of drugs that could overcome acquired resistance to MTAs."

Journal • HDAC2

Synthesis and identification of heteroaromatic N-benzyl sulfonamides as potential anticancer agents. (PubMed, Org Biomol Chem) - "The cell viability investigation identifies a subset of N-benzylic sulfonamides derived from the indole scaffold to be targeted for further development into novel molecules with potential therapeutic value. The most cytotoxic of the compounds prepared, AAL-030, exhibited higher potency than other well-known anticancer agents Indisulam and ABT-751."

Journal

Synthesis and biological evaluation of 1-benzyl-N-(2-(phenylamino)pyridin-3-yl)-1H-1,2,3-triazole-4-carboxamides as antimitotic agents. (PubMed, Bioorg Chem) - "Furthermore, 7f exhibited comparable tubulin polymerization inhibition (IC value 2.04 µM) to the standard E7010 (IC value 2.15 µM). Furthermore, molecular docking studies indicated that compound 7f binds to the colchicine binding site of the β-tubulin. Thus, 7f exhibits anti-proliferative properties by inhibiting the tubulin polymerization through the binding at the colchicine active site and by induction of apoptosis."

Journal

ABT-751 in Treating Children With Neuroblastoma That Has Relapsed or Not Responded to Previous Treatment (clinicaltrials.gov) - P2; N=92; Completed; Sponsor: Children's Oncology Group; Active, not recruiting ➔ Completed

Clinical • Trial completion

Synthesis of Novel Pyrazole Derivatives and Their Tumor Cell Growth Inhibitory Activity. (PubMed, Molecules) - "The most active compound 5b was much more potent than ABT-751 against K562 and A549 cells with GI values of 0.021 and 0.69 M, respectively. Moreover, 5b was identified as a novel tubulin polymerization inhibitor with an IC of 7.30 M."

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