elacridar (GF120918) / GSK - LARVOL DELTA

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indicated that resistant cells maintained under irinotecan pressure exhibited a multidrug-resistant phenotype, while withdrawn cells regained sensitivity, particularly to tyrosine kinase inhibitors.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

Enhancing Chemotherapeutic Efficacy by Combining Efflux Transporter Inhibition with CED Using a Novel sEEG-based Drug Delivery System (ASGCT 2025) - "In mouse models of DMG, topotecan concentrations in the midbrain were significantly higher after CED infusion (20 µL of 100 µM topotecan) when mice were pre-treated with either everolimus (5 mg/kg/day) or elacridar (100 mg/kg/day) for 5 days prior to topotecan infusion. Future studies will focus on testing CED with topotecan and oral everolimus in a large animal model. Disease Focus of Abstract:Cancer Solid Tumors"

Clinical • Brain Cancer • CNS Disorders • CNS Tumor • Diffuse Midline Glioma • Glioma • 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

Analysis of drug transporter expression in syncytiotrophoblast derived from human placental stem cells: Expression and function of efflux transporters. (PubMed, Placenta) - "This study showed higher transporter expression in ST-TSCT than that in a traditional trophoblast model. Furthermore, the functional expression of efflux transporters was observed. ST-TSCT is valuable for investigating placental transport functions."

Journal • Breast Cancer • Oncology • Solid Tumor • ABCB1 • ABCC2 • ABCG2

Integrative analysis based on CRISPR screen identifies apilimod as a potential therapeutic agent for cisplatin-induced acute kidney injury treatment. (PubMed, Sci China Life Sci) - "Apilimod and elacridar emerged as the top two candidates of mitigating cisplatin-induced nephrotoxicity, with apilimod demonstrating superior efficacy in drug matrix experiments. Additionally, apilimod treatment did not compromise the antitumor effect of cisplatin in cancer cells or tumor-bearing mice. Overall, our study suggests that apilimod could be a promising therapeutic agent for the treatment of cisplatin-induced AKI and revealed its underlying molecular mechanism."

Journal • Acute Kidney Injury • Metabolic Disorders • Nephrology • Oncology • Renal Disease • TFEB

Neuroprotective effects of SGLT2 inhibitors empagliflozin and dapagliflozin on Aβ1-42-induced neurotoxicity and neuroinflammation in cellular models of Alzheimer's disease. (PubMed, J Alzheimers Dis) - "However, the tested treatments did not modify the Aβ1-42-stimulating effect of HDAC6. Gliflozins are substrates of drug transporters ATP-binding cassette sub-family B member 1 and/or ATP binding cassette subfamily G member 2 (ABCB1 and ABCG2), and Elacridar significantly enhances their brain distribution.ConclusionsSGLT2i empagliflozin and dapagliflozin exhibited neuroprotective actions against human Aβ1-42-induced neurotoxicity."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • Inflammation • ABCB1 • ABCG2 • ANXA5 • CDK5 • NLRP3

The Role of Elacridar, a P-gp Inhibitor, in the Re-Sensitization of PAC-Resistant Ovarian Cancer Cell Lines to Cytotoxic Drugs in 2D and 3D Cell Culture Models. (PubMed, Int J Mol Sci) - "This study evaluated elacridar (GG918 and GF120918), a potent third-generation P-gp inhibitor, for its ability to reverse MDR in paclitaxel (PAC)-resistant ovarian cancer cell lines...Elacridar effectively inhibited P-gp activity and increased sensitivity to PAC and doxorubicin (DOX) in 2D cultures but not cisplatin (CIS)...These findings suggest that elacridar effectively inhibits P-gp in both 2D and 3D conditions. However, its ability to overcome drug resistance in 3D models is limited, highlighting the complexity of tissue-specific resistance mechanisms."

Journal • Preclinical • Oncology • Ovarian Cancer • Solid Tumor • ABCB1

ABT, Elacridar and Bile-Duct Cannulated Rats: Tools to Understand Pharmacokinetics. (PubMed, ChemMedChem) - "Over the years, molecular tools and experimental strategies have been developed to better understand the fate of compounds. Among these, the use of aminobenzotriazole (ABT), elacridar and bile-duct cannulated rats have been instrumental in gaining valuable PK insights, with a direct impact on drug design."

Journal • PK/PD data • Preclinical • Review • Cholangiocarcinoma • Solid Tumor

Brain distribution study of [14C]-Riluzole following intranasal administration in mice. (PubMed, Int J Pharm) - "Additionally, the impact of elacridar (ELC), an efflux pump inhibitor, on IN RLZ CNS bioavailability was examined. Further metabolic research using Chromatography-Mass spectrometry (LC-MS) or NMR along with excretion studies are warranted for a more comprehensive understanding of the pharmacokinetics of intranasal RLZ and intranasal RLZ/ELC. Additionally, employing suitable ALS animal models is crucial for understanding RLZ's effects on disease progression, mechanism of action, efficacy, and potential side effects to aid further development."

Journal • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders