elacridar (GF120918) / GSK - LARVOL DELTA

Improvement of the Intestinal Absorption of Dihydroquercetin (DHQ) by Flavonoids via Inhibiting P-Glycoprotein (P-gp)-Mediated Efflux in P-gp Overexpressed KB/MDR1 Cells and Caco-2 Monolayers. (PubMed, J Agric Food Chem) - "The low uptakes of DHQ were dynamically increased by four FIs (better than elacridar) in the order of quercetin > luteolin > kaempferol > flavone...Docking results explained that quercetin competitively occupies DHQ's binding site or binds to the inhibitor site of P-gp. These results were valuable for improving DHQ absorption."

Journal • ABCB1

Utilization of a UPLC-MS/MS Approach to Elucidate the Role of ABCB1-Mediated Paclitaxel Resistance in Non-Small Cell Lung Cancer Cells. (PubMed, Oncol Res) - "Genetic silencing of ABCB1 or pharmacological inhibition with the specific P-glycoprotein modulator elacridar or tariquidar restored intracellular paclitaxel levels, as determined by UPLC-MS/MS, and synergistically decreased cell viability as observed in CCK-8 assay. These findings reveal that the ABCB1-mediated drug efflux is a crucial mechanism underlying paclitaxel resistance in NSCLC cells, with UPLC-MS/MS serving as a sensitive analytical method to detect paclitaxel concentration. Inhibition of ABCB1 is a promising therapeutic strategy to resensitize resistant tumor cells to paclitaxel."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCB1

Visualizing the Functional Dynamics of P-Glycoprotein and Its Modulation by Elacridar via High-Speed Atomic Force Microscopy. (PubMed, Int J Mol Sci) - "Our direct observations revealed that low concentrations induced active dynamics in P-gp, whereas high concentrations severely restricted its motion, leading to a rigid, non-productive state. Our study provides critical insights into how observing molecular motion itself can unravel complex biological mechanisms."

Journal • Breast Cancer • Oncology • Solid Tumor

Characterization of EpiIntestinal Duodenum Microtissue as an In Vitro Model for Studying Intestinal Drug Permeability, Transport, and Metabolism. (PubMed, Pharm Res) - "These findings suggest that the EpiIntestinal duodenum microtissue can effectively replicate the complex interplay of permeability, metabolism, and transport in the gut, thereby improving the prediction of oral drug absorption."

Journal • Preclinical • CYP2C19 • CYP3A4 • UGT1A1

Elacridar Reverses P-gp-Mediated Drug Resistance in Ovarian Cancer Cells in 2D and 3D Culture Models. (PubMed, Int J Mol Sci) - "In this study, we evaluated the ability of elacridar, a dual P-gp and BCRP inhibitor, to overcome MDR in W1, an ovarian cancer cell line sensitive to Paclitaxel (PAC) and its PAC-resistant variants. These findings highlight elacridar as a promising compound for reversing MDR in ovarian cancer and emphasize the importance of 3D models in preclinical drug evaluation. Further studies in advanced in vitro and in vivo models are required to assess the potential of elacridar better."

Journal • Platinum sensitive • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • ABCB1

P-gp/BCRP efflux and intestinal metabolism limit tigecycline exposure: Effects of elacridar and voriconazole in mice. (PubMed, Drug Metab Dispos) - "Because bacterial efflux pumps that expel tetracyclines are homologous to mammalian P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), we investigated whether these transporters, along with TIG metabolism, affect TIG pharmacokinetics in mice. SIGNIFICANCE STATEMENT: Blocking efflux pumps by elacridar in the gut, liver, and brain increases tigecycline absorption and systemic retention. Coadministration of voriconazole, an inhibitor of metabolism, also suggests a significant role of intestinal metabolism in restricting tigecycline's oral bioavailability."

Journal • Preclinical • Breast Cancer • CNS Disorders • Oncology • Solid Tumor

Intracerebral Distribution of Drugs with Diverse Blood-brain Barrier Transport Characteristics: In vivo Analysis using Brain Microdialysis in Cynomolgus Monkeys. (PubMed, Pharm Res) - "The results of this study suggest that the intracerebral distribution of the test drugs from the blood in the monkey brain should consider the contribution of influx transporters as well as efflux transporters. In addition, the lumbar CSF concentrations of the test drugs appear to be a useful surrogate marker of the ISF concentrations."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor

Enhanced Lysosomal Activity Prevents Infection with PrPSc and the Seeding Activity of α-Synuclein & Tau Prions. (PubMed, J Biol Chem) - "Surprisingly, these effects occur independently of TFEB nuclear translocation, suggesting novel regulatory mechanisms. The anti-prion effects of elacridar extend to α-synuclein and tau prions, highlighting lysosomal enhancement as a general strategy for treatment of protein misfolding neurodegenerative diseases."

Journal • CNS Disorders • Infectious Disease • Metabolic Disorders • TFEB

Targeting type I PRMTs in ALS: in vivo evaluation of MS023 and GSK3368715 in TDP43Q331K and SOD1G93A mice (ALS-MND 2025) - "Higher CNS exposures of MS023 and GSK3368715, were achieved using elacridar (50 mg/kg, PO), a P-glycoprotein inhibitor, which was therefore used in all subsequent studies. Both compounds were well-tolerated up to 50 mg/kg, with higher doses causing weight loss. In TDP43Q331K mice, plasma ADMA levels were elevated relative to wild-type controls and were reduced by GSK3368715, but not by MS023."

Preclinical • Plasma NfL • TARDBP

The Resistance Mechanism to BET-Protac in Multiple Myeloma (ASH 2023) - "AR1 and AR2 cells showed decreased sensitivity to ARV-825, MZ-1, OTX-015, I-BET151, Daunorubicin and Epirubicin...Combined use of ABCB1 inhibitors (verapamil, cyclosporin A, Elacridar) or knockout of ABCB1 could significantly reduce the IC50 of drug-resistant cells, increase the apoptosis rate after ARV-771 treatment, and increase the degradation of BRD4 and the down-regulation of c-Myc... Our results showed that BET-PROTAC resistance in MM cells wasindependent of β-catenin activation. The up-regulation of ABCB1 expression was the key mechanism mediating the resistance of myeloma cells to BET-PROTAC. C1orf112, CCDC167 and CRIP2 might be associated with drug resistance in myeloma and could affect prognosis, and their mechanisms in myeloma need to be further investigated."

Hematological Malignancies • Multiple Myeloma • Oncology • Targeted Protein Degradation • ABCB1 • BRD4 • MYC • TCF7

Phenotypic plasticity including drug efflux drives reversible irinotecan resistance in LIM1215 colorectal cancer cells. (PubMed, FEBS Lett) - "Drug screening further indicated that resistant cells maintained under irinotecan pressure exhibited a multidrug-resistant phenotype, while withdrawn cells regained sensitivity, particularly to tyrosine kinase inhibitors. Supplementation with the efflux inhibitor Elacridar partially restored drug sensitivity in resistant cells, emphasizing the role of transporter-mediated efflux in maintaining resistance."

Journal • Colorectal Cancer • Oncology • Solid Tumor • ABCB1 • ABCG2

Predictors of response and rational combinations for the novel MCL-1 inhibitor MIK665 in acute myeloid leukemia. (PubMed, Mol Oncol) - "To induce sensitivity, we treated MIK665-resistant samples with ABCB1 inhibitors elacridar or tariquidar, BCL-XL inhibitor A1331852, or BCL-2 inhibitor venetoclax in combination with MIK665. Additionally, the combination of MIK665 with venetoclax restored sensitivity in samples with primary venetoclax resistance. Overall, this study indicates that elevated ABCB1 expression is a potentially targetable resistance mechanism in the context of MIK665 resistance, and that a combination of MIK665 with venetoclax may be effective for overcoming resistance to either MCL-1 or BCL-2 inhibition."

IO biomarker • Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ABCB1 • BCL2L1

Molecular effects of paclitaxel-elacridar nanoemulsions in breast cancer cells: impact on uptake, cell cycle and signaling pathways. (PubMed, Eur J Pharm Biopharm) - "Apoptosis was maintained as the main mechanism of cell death. The formulation also reduced cell migration (3-fold) compared to the solution at concentrations lower than IC50, while the clonogenic effect (17-fold) was not hindered, supporting a broader impact on tumorigenesis."

IO biomarker • Journal • B Cell Lymphoma • Breast Cancer • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • BCL2

Lysosomal Enhancement Prevents Infection with PrP Sc , α-Synuclein & Tau Prions. (PubMed, bioRxiv) - "Surprisingly, these effects occur independently of TFEB nuclear translocation, suggesting novel regulatory mechanisms. The anti-prion effects of elacridar extend to α-synuclein and tau prions, highlighting lysosomal enhancement as a general strategy for the treatment of protein misfolding neurodegenerative diseases."

Journal • CNS Disorders • Infectious Disease • Metabolic Disorders • TFEB

Elacridar improves sunitinib efficacy in colorectal cancer models. (PubMed, Eur J Pharm Sci) - "Storage of drugs-that are lysosomotropic and substrates of ABC-transporters-in subcellular compartments reduces the active pool and potentially contributes to intrinsic drug resistance in mCRC. Combination strategies that target ABC-transporters or lysosomes might be considered to potentiate drug efficacy."

Journal • Preclinical • Colorectal Cancer • Oncology • Solid Tumor

The role of drug efflux and uptake transporters in the plasma and tissue disposition of KRASG12D inhibitor MRTX1133 (EACR 2025) - P1 | "To date, there are no FDA-approved KRAS inhibitors other than Sotorasib and Adagrasib, which target uniquely the KRASG12C mutation. This study highlights the relevance of ABCB1/ABCG2 in the transporter-mediated restriction of brain penetration and reduction of kidney and liver accumulation of MRTX1133. We hypothesize that co-administration of the dual ABCB1/ABCG2 inhibitor elacridar could promote brain penetration and increase kidney and liver exposure for MRTX1133. The insights gained may contribute to enhancing the safety and efficacy of MRTX1133 in the clinic."

Biliary Cancer • Cholangiocarcinoma • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • ABCB1 • ABCG2 • KRAS • SLCO1C1

In Vivo Characterization of [18F]ASEM as PET Radioligand of Engineered α7 Nicotinic Acetylcholine Receptors (SNMMI 2025) - "The dynamic PET imaging studies were acquired after intravenous injection of [18F]ASEM at baseline, after self-block (1 mg/kg) alone, and self-block (1 mg/kg) plus elacridar (3 mg/kg) for blood-brain barrier efflux transporter block... [18F]ASEM showed a good brain update in the PSAM4-GlyR transduced monkey at baseline and after pharmacological challenges (Fig. 1B). [18F]ASEM demonstrated higher target (PSAM4-GlyR injection site, left-amygdala) uptake compared to the mirror (contralateral site, right-amygdala) under baseline condition (Fig."

Preclinical • CNS Disorders • Mental Retardation • Psychiatry

Evaluation of [18F]JHU94620-d8 as a candidate PET radiotracer for brain CB2R imaging: metabolic stability, neuroinflammation detection, and efflux transporter interactions (SNMMI 2025) - "The efflux transporter substrate potential of [18F]JHU94620-d8 was evaluated using wild-type mice (n=3), mice with dual P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) knockout (n=2), and monkey (n=1) pre-treated with elacridar (3mg/kg), a dual P-gp/BCRP inhibitor... [18F]JHU94620-d8 showed quick brain uptake in healthy rats and monkeys under baseline and CB2R blocked conditions. In monkey, the distribution volume corrected for free fraction in plasma (VT/fP) was comparable between baseline and blocked conditions. Receptor blockade in monkeys indicated low to no specific radioactivity uptake after [18F]JHU94620-d8 injection; a similar result was observed in rats."

Breast Cancer • Inflammation • Oncology • Solid Tumor

Radiosynthesis and Preclinical PET Imaging of ALK2-Selective 3,5-Diphenylpyridine Inhibitors for a Rare Pediatric Brainstem Cancer (SNMMI 2025) - "Pharmacokinetic and pharmacodynamic properties were evaluated through PET imaging in male and female rodents at baseline, 30 min after pre-treatment with elacridar (5 mg/kg), or after combined elacridar pre-treatment with homologous blocking. Conclusion . A new series of radiolabeled 3,5-diphenylpyridines were synthesized and biologically evaluated to identify critical structural features that affect pontine tissue exposure. Significant improvements in brain permeability and radiometabolic stability were achieved compared to previous structures (e.g."

Preclinical • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • ACVR1

Radiosynthesis and Preclinical PET Imaging of ALK2-Selective 3,5-Diphenylpyridine Inhibitors for a Rare Pediatric Brainstem Cancer (SNMMI 2025) - "Pharmacokinetic and pharmacodynamic properties were evaluated through PET imaging in male and female rodents at baseline, 30 min after pre-treatment with elacridar (5 mg/kg), or after combined elacridar pre-treatment with homologous blocking. Conclusion . A new series of radiolabeled 3,5-diphenylpyridines were synthesized and biologically evaluated to identify critical structural features that affect pontine tissue exposure. Significant improvements in brain permeability and radiometabolic stability were achieved compared to previous structures (e.g."

Preclinical • Brain Cancer • Diffuse Intrinsic Pontine Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • ACVR1

Evaluation of [18F]JHU94620-d8 as a candidate PET radiotracer for brain CB2R imaging: metabolic stability, neuroinflammation detection, and efflux transporter interactions (SNMMI 2025) - "The efflux transporter substrate potential of [18F]JHU94620-d8 was evaluated using wild-type mice (n=3), mice with dual P-glycoprotein (P-gp) and breast cancer resistant protein (BCRP) knockout (n=2), and monkey (n=1) pre-treated with elacridar (3mg/kg), a dual P-gp/BCRP inhibitor... [18F]JHU94620-d8 showed quick brain uptake in healthy rats and monkeys under baseline and CB2R blocked conditions. In monkey, the distribution volume corrected for free fraction in plasma (VT/fP) was comparable between baseline and blocked conditions. Receptor blockade in monkeys indicated low to no specific radioactivity uptake after [18F]JHU94620-d8 injection; a similar result was observed in rats."

Breast Cancer • Inflammation • Oncology • Solid Tumor

In Vivo Characterization of [18F]ASEM as PET Radioligand of Engineered α7 Nicotinic Acetylcholine Receptors (SNMMI 2025) - "[18F]ASEM showed a good brain update in the PSAM4-GlyR transduced monkey at baseline and after pharmacological challenges (Fig. 1B). [18F]ASEM demonstrated higher target (PSAM4-GlyR injection site, left-amygdala) uptake compared to the mirror (contralateral site, right-amygdala) under baseline condition (Fig."

Preclinical • CNS Disorders • Mental Retardation • Psychiatry

Functional Implications of the Conformational Landscape of a Multidrug Transporter Revealed by Structures of Zebrafish Abcb4. (PubMed, bioRxiv) - "This global open-and-close motion is coupled with individual helix movement, resulting in a highly fluid substrate-binding pocket. These dynamic changes, likely underlying the polyspecificity of substrate recognition, predict unconventional protein-ligand interactions that are supported by structures of Abcb4 bound to the P-gp inhibitors tariquidar and elacridar, and the substrate vincristine."

Journal • ABCB1 • ABCB4

Elacridar Inhibits BCRP Protein Activity in 2D and 3D Cell Culture Models of Ovarian Cancer and Re-Sensitizes Cells to Cytotoxic Drugs. (PubMed, Int J Mol Sci) - "A key contributor to this resistance is the overexpression of ATP-binding cassette (ABC) transporters, including breast cancer resistance protein (BCRP/ABCG2), which actively effluxes chemotherapeutic agents such as topotecan (TOP) or mitoxantrone (MIT), limiting their intracellular accumulation and efficacy. In both 2D and 3D cultures, elacridar effectively inhibited BCRP function and significantly enhanced sensitivity to TOP. These findings suggest that elacridar can inhibit BCRP-mediated drug resistance in ovarian cancer cell models."

Journal • Preclinical • Breast Cancer • Oncology • Ovarian Cancer • Solid Tumor • ABCG2

Lipidomic analysis of MDCK-parental cells and MDCK-MDR1 cells exposed to GF120918 and clarithromycin highlights the role of P-glycoprotein in sphingolipid transport. (PubMed, Biochimie) - "These results support the hypotheses of a role for P-gp as well as glucosylceramide flippase within the Golgi apparatus of cells. It also provides a proof of concept for understanding pharmaco-metabolomic results in the study of drug transporters in humans."

Journal • ABCB1