zosuquidar (LY335979) / Kanisa Pharma, Eli Lilly - LARVOL DELTA

A Nanodrug Self-Assembled from a Redox-Responsive Cabazitaxel-Zosuquidar Conjugate and DSPE-PEG2k Reverses Multidrug Resistance in Nonsmall Cell Lung Cancer. (PubMed, ACS Appl Bio Mater) - "The in vivo tumor inhibition rate of CZNPs reaches up to 86.91% in A549/PTX tumor-bearing mice without obvious toxic side effects. These smart CZNPs may offer a promising clinical treatment approach for drug-resistant NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

In vitro assessment of ATP-binding cassette transporters and their functional genetic polymorphisms on fluoroquinolone accumulation in human embryonic kidney 293 recombinant cell lines. (PubMed, Drug Metab Dispos) - "This study assesses the impact of these transporters on moxifloxacin and ciprofloxacin (CIP) cellular accumulation in vitro, and the effect of common single-nucleotide polymorphisms in ABCB1 [c.1199G>A (rs2229109); common haplotype c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642)] and ABCG2 [c.421C>A (rs2231142)]...Results indicated that ABCB1 overexpression reduced moxifloxacin cellular concentration by 30% but inconsistently with that of CIP and that zosuquidar or elacridar reversed these effects...Specific ABCB1 polymorphisms (CGT and TTT haplotypes) reduce the ABCB1 transport capacity toward fluoroquinolones. These findings highlight the importance of considering ABCB1 and ABCC4 inducers or inhibitors, which may affect fluoroquinolone disposition in tissues and cells, as well as ABCB1 polymorphisms that could explain interindividual variability in pharmacokinetic profiles."

Journal • Preclinical • ABCB1 • ABCG2

The oral bioavailability of a pleuromutilin antibiotic candidate is increased after co-administration with the CYP3A4 inhibitor ritonavir and the P-gp inhibitor zosuquidar formulated as amorphous solid dispersions. (PubMed, Int J Pharm) - "The combined co-administration of ritonavir- and zosuquidar-containing ASDs surprisingly increased CVH-174 bioavailability to around 18 %. In conclusion, the oral bioavailability of CVH-174 can be significantly increased through a formulation design encompassing an inhibitor of the CYP3A4 enzyme, and this holds great potential for the future development of an inherent metabolic labile pleuromutilin drug class."

Journal

In vitro analysis of the activities of commercial anthelmintics in the presence of inhibitors of xenobiotic detoxification pathways in Haemonchus contortus exsheathed L3 stage. (PubMed, Parasitol Res) - "To explore this hypothesis, inhibitors of xenobiotic detoxification pathways were tested on the activity (IC50) of four anthelmintics-monepantel (MOP), levamisole (LEV), ivermectin (IVM), and albendazole sulfoxide (ABZ SO)-in xL3 using an automated motility assay. The inhibitors used were piperonyl butoxide (PBO) for phase I metabolism, 5-nitrouracil (5-NU) for phase II metabolism, and zosuquidar (ZOS) inhibiting efflux transport proteins...The use of inhibitors of xenobiotic detoxification pathways led to significant changes in the in vitro activity of the anthelmintics evaluated in H. contortus xL3 stage. Further studies, as ex vivo parasite diffusion assays in the xL3 stage, should be conducted to directly assess the impact on detoxification pathways."

Journal • Preclinical • Infectious Disease

The "specific" P-glycoprotein inhibitor zosuquidar (LY335979) also weakly inhibits human organic cation transporters. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "This still has to be kept in mind when zosuquidar is used to inhibit cellular efflux of P-gp substrates that are concurrently transported into the cells by OCTs. To avoid interference in these assays, zosuquidar concentrations should be kept below 1 µM."

Journal

Soloxolone N-3-(Dimethylamino)propylamide Restores Drug Sensitivity of Tumor Cells with Multidrug-Resistant Phenotype via Inhibition of P-Glycoprotein Efflux Function. (PubMed, Molecules) - "Blind and site-specific molecular docking accompanied by a kinetic assay showed that 4 directly binds to the P-gp transmembrane domain with a binding energy similar to that of zosuquidar, a third-generation P-gp inhibitor (ΔG = -10.3 kcal/mol). In vitro assays confirmed that compound 4 enhanced the uptake of Rhodamine 123 (Rho123) and doxorubicin (DOX) by the P-gp-overexpressing human cervical carcinoma KB-8-5 (by 10.2- and 1.5-fold, respectively (p < 0.05, unpaired t-test)) and murine lymphosarcoma RLS40 (by 15.6- and 1.75-fold, respectively (p < 0.05, unpaired t-test)) cells at non-toxic concentrations. In these cell models, 4 showed comparable or slightly higher activity than the reference inhibitor verapamil (VPM), with the most pronounced effect of the hit compound in Rho123-loaded RLS40 cells, where 4 was 2-fold more effective than VPM. Moreover, 4 synergistically restored the sensitivity of KB-8-5 cells to the cytotoxic effect of DOX, demonstrating MDR..."

Journal • Tumor cell • Cervical Cancer • Oncology • Sarcoma • Solid Tumor

Heteroaryl derivatives of suvorexant as OX1R selective PET ligand candidates: Cu-mediated 18F-fluorination of boroxines, in vitro and initial in vivo evaluation. (PubMed, EJNMMI Res) - "The in vitro and in vivo results of [18F]1c and [18F]1f provide a solid basis for further development of suitable OXR PET ligands for brain imaging."

Journal • Preclinical • CNS Disorders • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Psychiatry • Solid Tumor • Substance Abuse

Zosuquidar Promotes Antitumor Immunity by Inducing Autophagic Degradation of PD-L1. (PubMed, Adv Sci (Weinh)) - "In CT26 mouse model and a humanized xenograft mouse model, zosuquidar significantly suppresses tumor growth and accompanies by increased infiltration of cytotoxic T cells. In summary, this study indicates that ABCB1 serves as a negative regulator of PD-L1, and zosuquidar may act as a potential immunotherapy agent by triggering PD-L1 degradation in the early secretory pathway."

IO biomarker • Journal • Oncology • ABCB1 • PD-L1 • SQSTM1

Mutational analysis reveals the importance of residues of the access tunnel inhibitor site to human P-glycoprotein (ABCB1)-mediated transport. (PubMed, Protein Sci) - "Surprisingly, after the mutations were introduced, inhibitors such as tariquidar and zosuquidar still inhibited drug efflux by mutant P-gps...In silico molecular docking studies corroborated the altered inhibitor binding due to mutations in the L-site residues, shedding light on their critical role in substrate transport and inhibitor interactions with P-gp. These findings suggest that inhibitors bind either to the SBP alone, and/or to alternate site(s) when the L-site is disabled by mutagenesis."

Biomarker • Journal • Oncology • ABCB1

Preclinical efficacy and safety of M9140, a novel antibody-drug conjugate (ADC) with topoisomerase 1 (TOP1) inhibitor payload targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)‑expressing colorectal tumors (AACR 2024) - P1 | "Potency shift viability assays were conducted using two CRC cell lines, with zosuquidar used as multidrug resistance-1 (MDR-1) inhibitor... M9140 demonstrated high potency, strong antitumor activity, and bystander effect in preclinical models. The side effect profile in monkeys was favorable and in line with the expected toxicity of exatecan. Notably, ILD and ocular toxicity, which are known adverse effects of deruxtecan and maytansine-based ADCs respectively, were absent."

Preclinical • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • ABCB1 • CEACAM5 • TOP1

Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer. (PubMed, Proc Natl Acad Sci U S A) - "AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise."

Journal • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor • Targeted Protein Degradation • ABCB1 • AR • PBRM1 • SMARCA2 • SMARCA4

A convenient protonated strategy for constructing nanodrugs from hydrophobic drug-inhibitor conjugates to reverse tumor multidrug resistance. (PubMed, Nanoscale) - "Specifically, paclitaxel (PTX) is first coupled with a third-generation P-glycoprotein (P-gp) inhibitor zosuquidar (Zos) through a glutathione (GSH)-responsive disulfide bond to produce a hydrophobic drug-inhibitor conjugate (PTX-ss-Zos). Once internalized by cancer cells, PTX-ss-Zos@HCl NPs can be degraded under the overexpressed GSH to release PTX and Zos simultaneously, which synergistically reverse tumor MDR and inhibit tumor growth. This offers a promising strategy to develop small molecule self-assembled nanoagents to reverse tumor MDR in combination therapy."

Journal • Oncology

Zosuquidar: An Effective Molecule for Intracellular Ca2+ Measurement in P-gp Positive Cells. (PubMed, Int J Mol Sci) - "The solution is to use a proper inhibitor of P-gp efflux activity to ensure the retention of the tracer inside the cells. The present study showed that Zosuquidar and Tariquidar (P-gp inhibitors) are suitable for monitoring intracellular calcium, either by flow cytometry or confocal microscopy, in cells overexpressing P-gp."

Journal • Oncology • ABCB1

Continuous 72-h infusion of zosuquidar with chemotherapy in patients with newly diagnosed acute myeloid leukemia stratified for leukemic blast P-glycoprotein phenotype. (PubMed, Cancer Chemother Pharmacol) - P1/2 | "These observations provide evidence of Zos efficacy with the 72-h CIV infusion approach. The similarity of ORR in the P-gp-high and P-gp-low subgroups is consistent with Zos-mediated neutralization of P-gp as verified by PD analyses. The bioassay identified sAML patients most likely to respond favorably to Zos co-therapy indicating feasibility as a Zos companion diagnostic. A follow-up placebo-controlled trial is needed to verify these promising results."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

Consensus screening for a challenging target: the quest for P-glycoprotein inhibitors. (PubMed, RSC Med Chem) - "With this consensus approach, 13 potential candidates were identified and then tested for their ability to inhibit P-gp, using zosuquidar, a third generation P-gp inhibitor, as a reference drug...Both retrospective and prospective results demonstrate the ability of the combined structure-based pharmacophore modeling and docking-based virtual screening approach to predict novel hit compounds with inhibitory activity toward P-gp. The resulting chemical scaffolds could serve as inspiration for the optimization of novel and more potent P-gp inhibitors."

Journal • Oncology • ABCB1

Inhibition of the transmembrane transporter ABCB1 overcomes resistance to doxorubicin in patient-derived organoid models of hepatocellular carcinoma (LCS 2024) - "Most importantly, inhibition of ABCB1 with elacridar and zosuquidar increased intracellular doxorubicin levels and thereby restored doxorubicin efficacy in resistant HCCOs. ABCB1 overexpression is an important resistance mechanism of HCC cells contributing to non-response to doxorubicin. The pharmacological inhibition of the drug export pump ABCB1 is a promising strategy to increase response to TACE and should be further explored in clinical trials."

Clinical • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • ABCB1