elacridar (GF120918) / GSK - LARVOL DELTA

STAT3 Targeting in Brain Metastases: Pharmacokinetic Barriers to JAK/STAT3 Inhibition (EANO 2026) - "However, whether effective STAT3 inhibition can be achieved within the brain metastatic microenvironment at clinically relevant drug exposures remains unclear. We systematically evaluated the brain penetration and transporter affinity of five FDA-approved JAK inhibitors (baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib) using in vitro transporter assays and in vivo pharmacokinetic studies in wild-type and ABCB1/ABCG2-deficient mice...At clinically relevant exposures in wild-type mice, neither compound meaningfully inhibited STAT3 phosphorylation in tumor cells or reactive astrocytes, even in the presence of the pharmacological ABCB1/ABCG2 inhibitor elacridar. Approved JAK/STAT3 inhibitors lack the pharmacokinetic properties required to achieve sufficient STAT3 target engagement in the brain metastatic microenvironment at clinically relevant exposures. These findings highlight the critical need to incorporate BBB transport and human-relevant exposure..."

PK/PD data • Breast Cancer • Melanoma • Oncology • Solid Tumor • ABCB1 • ABCG2

Development and Preclinical Evaluation of a Novel PET Probe for Phosphodiesterase 7B Imaging in Brain. (PubMed, ACS Chem Neurosci) - "Pretreatment with elacridar, a potent dual inhibitor of drug efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), enhanced the brain uptake of [11C]5, resulting in further specific in vivo binding in the olfactory bulb and striatum. In conclusion, although the brain permeability of [11C]5 was limited by P-gp and BCRP, [11C]5 demonstrated specific binding to PDE7B, both in vitro and in vivo, supporting its potential utility for imaging PDE7B in the central nervous system."

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

Multifunctional nanoparticles for co-delivery of elacridar and paclitaxel for breast cancer local treatment. (PubMed, Int J Pharm) - "In an in vivo model of breast cancer, intraductal H-NPs reduced tumor incidence and volume compared to a drug solution, and increased the mammary tissue-to-plasma ratio of paclitaxel by 105-fold, supporting an improved tissue retention. These findings support H-NPs as promising platforms for localized breast cancer therapy."

Journal • Breast Cancer • Oncology • Solid Tumor

Preliminary pharmacokinetic investigation of two discoidin domain receptor 2 inhibitors in murine plasma and brain using liquid chromatography-tandem mass spectrometry analysis. (PubMed, Sci Rep) - "In addition, five prediction software tools were used to estimate pharmacokinetic parameters relevant to the BBB penetration of the two compounds. Finally, the method was applied in preclinical pharmacokinetic studies using elacridar, an efflux transporter inhibitor."

Journal • PK/PD data • Preclinical • CNS Disorders • Oncology • DDR2

Functional implications of the conformational landscape of a multidrug transporter revealed by Zebrafish Abcb4 structures. (PubMed, Nat Commun) - "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 DrAbcb4 bound to the P-gp inhibitors tariquidar and elacridar, and the substrate vincristine."

Journal • ABCB1 • ABCB4

Hydroxynicotinamide-based PET radioligands bind selectively to histone deacetylase 6 but are substrates for efflux transporters in rodent and monkey brain (SNMMI 2026) - "Efflux transporter involvement was examined in i) rats and monkeys pretreated with elacridar, ii) mice with dual P-gp/BCRP knockout, and iii) rats given the organic anion transporter (OAT) inhibitor probenecid. Both [¹⁸F]MM1 and [¹⁸F]MM2 exhibit clear, reproducible in vivo HDAC6-specific binding in rodent and primate brain. However, each is a substrate for major efflux transporters, substantially limiting their potential for human HDAC6 PET imaging. The similar imaging profiles of MM1 and MM2 indicate that fluorine-18 placement does not alleviate transporter susceptibility."

Epigenetic controller • Preclinical • CNS Disorders

Hydroxynicotinamide-based PET radioligands bind selectively to histone deacetylase 6 but are substrates for efflux transporters in rodent and monkey brain (SNMMI 2026) - "Efflux transporter involvement was examined in i) rats and monkeys pretreated with elacridar, ii) mice with dual P-gp/BCRP knockout, and iii) rats given the organic anion transporter (OAT) inhibitor probenecid. Both [¹⁸F]MM1 and [¹⁸F]MM2 exhibit clear, reproducible in vivo HDAC6-specific binding in rodent and primate brain. However, each is a substrate for major efflux transporters, substantially limiting their potential for human HDAC6 PET imaging. The similar imaging profiles of MM1 and MM2 indicate that fluorine-18 placement does not alleviate transporter susceptibility."

Epigenetic controller • Preclinical • CNS Disorders

Synergistic Enhancement of Chemotherapy via Efflux Transporter Inhibition and Convection-Enhanced Delivery Using a New sEEG-Based Drug Delivery System (ASGCT 2026) - "Mice were pretreated for five days with either everolimus or elacridar prior to CED. The ability to simultaneously deliver drugs and monitor neural activity offers a unique platform to assess local toxicity and long-term neuronal effects, particularly relevant for diffuse gliomas where tumor cells intermingle with functional neural tissue. Ongoing studies will evaluate combined CED topotecan and systemic everolimus in a large animal model and advancement to human clinical trials."

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

Enhanced antinociception of mixed efficacy opioid peptidomimetics through P-glycoprotein modulation. (PubMed, J Pharmacol Exp Ther) - "We hypothesized that crossing the blood-brain barrier was the limiting factor and tested the effects of AAH9 and AMB39 in combination with a P-glycoprotein inhibitor, Elacridar...One reason for this is the inability to reach the site of action. In this report, we describe 2 pairs of compounds with significantly different pharmacokinetic profiles and describe strategies for determining central nervous system penetration of opioid ligands."

Journal • Pain

Top2a-dependent neuronal regulation of social behavior and persistent rescue of social deficit through PRC2-mediated epigenetic reprogramming. (PubMed, bioRxiv) - "Pharmacological inhibition of PRC2 using the EZH2 inhibitor tazemetostat, combined with elacridar to facilitated blood-brain barrier penetration, robustly rescues social deficits in Top2a conditional knockout mice. These results showcase the unique capability of epigenetic modulatory therapy to induce durable behavioral improvements and their therapeutic potential for treating social dysfunction in neuropsychiatric disorders. Together, our results provide direct genetic evidence that neuronal Top2a governs social behavior in mice and establish the neuronal Top2a-PRC2 axis as a conserved, targetable epigenetic pathway regulating social behavior."

Journal • Autism Spectrum Disorder • CNS Disorders • Cognitive Disorders • Genetic Disorders • Mental Retardation • Psychiatry • TOP2A

Daraxonrasib (RMC-6236) pharmacokinetics: impact of transporters and drug-metabolizing enzymes on a first-in-class pan-RAS molecular glue. (PubMed, Pharmacol Res) - "Abcb1a/1b-mediated transport of daraxonrasib across the BBB was validated by oral co-administration of the ABCB1/ABCG2 inhibitor elacridar, resulting in 20-fold increased brain penetration in wild-type mice (P < 0.01). ABCB1 function could limit brain penetration and possibly efficacy of daraxonrasib against brain metastases. Collectively, these preclinical findings may help in optimizing the application of daraxonrasib in clinical settings."

Journal • PK/PD data • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • Targeted Protein Degradation • ABCB1 • ABCG2 • CYP3A4 • KRAS

OB-001 Enhances Osimertinib Brain Penetration: Preclinical Pharmacokinetics and Translational Rationale for EGFR-Mutant NSCLC with CNS Disease. (PubMed, Cancer Res Commun) - "OB-001, a KinetiSol® amorphous solid dispersion formulation of elacridar, was developed to overcome poor bioavailability of crystalline elacridar and evaluated as a strategy to enhance osimertinib brain delivery. OB-001 selectively boosts osimertinib brain exposure while sparing systemic PK. These preclinical data support further evaluation of OB-001 as a strategy to enhance CNS efficacy of osimertinib in EGFR-mutant NSCLC."

Journal • PK/PD data • Preclinical • CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCB1 • ABCG2 • EGFR

Pharmacological strategies to enhance the response of hepatoblastoma to chemotherapy through MDR1 inhibition. (PubMed, Acta Pharmacol Sin) - "Curcumin did not sensitize HepG2-DR cells to doxorubicin, whereas verapamil and simvastatin enhanced doxorubicin cytotoxicity only at toxic concentrations. In contrast, several TKIs, including nilotinib, tivozanib, and, to a lesser extent, cabozantinib, exhibited synergistic effects with doxorubicin in HepG2-DR cells...Third-generation MDR1 inhibitors (tariquidar, elacridar, and zosuquidar) sensitized HepG2-DR and HB-303 cells at non-toxic nanomolar concentrations in vitro...MDR1 inhibitors, such as zosuquidar, may enable dose reductions of chemotherapeutic agents, whereas the use of synergistic TKIs, such as tivozanib, may improve therapeutic outcomes and minimize adverse effects in children with HB. TG100-115, a TRPM7 kinase inhibitor, provides neuroprotection and attenuates NLRP3 inflammasome-mediated neuroinflammation in a neonatal mouse model of hypoxic-ischemic brain injury."

Journal • CNS Disorders • Hepatoblastoma • Liver Cancer • Oncology • Pediatrics • Solid Tumor • Vascular Neurology • ABCB1 • NLRP3 • TRPM7

Effects of the Antiretroviral Raltegravir on Amyloid-Beta1-42-Induced Neuroinflammation (IMMUNOLOGY 2026) - "We aim to evaluate the effect of raltegravir, either alone as a single therapy or combined with elacridar, a P-gp/BCRP inhibitor, on AD-related pathways in vitro. Flow cytometry combined was used to quantify the expression of key inflammatory markers, including interleukin-1β (IL-1β), NLRP3 inflammasome components, costimulatory molecules (CD86), and the class B scavenger receptor (SR-B2) CD163, in HMC3 human microglia cells. Taken together, our findings suggest that raltegravir exerts a neuroprotective effect by targeting pathological events associated with AD, particularly tau phosphorylation and neuroinflammation."

Alzheimer's Disease • Brain Cancer • CNS Disorders • Glioma • Infectious Disease • Inflammation • Neuroglioma • Solid Tumor • Aβ42 • CD163 • CD86 • IL1B • NLRP3

Elacridar sensitizes liver cancer to the PKC-inhibitor ICA-1S (AACR 2024) - "This resistance inflection may be due to several factors including the activation of drug-efflux proteins. Thus, we proved that the introduction of an efflux pump inhibitor, Elacridar, sensitizes the liver cancer cells to ICA-1S, offsets the resistance of the liver cancer cells to ICA-1S at high concentrations, and enables ICA-1S to be effective in downregulating PKC-ι and decreasing cell growth of liver cancer cells."

IO biomarker • Colorectal Cancer • Gastrointestinal Cancer • Liver Cancer • Oncology • Solid Tumor

Mapping the inhibition landscape of P-glycoprotein via conformational ensemble docking. (PubMed, Sci Rep) - "Known inhibitors such as tariquidar and elacridar (previously resolved in cryo-EM structures) validated the docking approach. Large macrocyclic inhibitors such as valspodar and cyclosporine preferred conformations with wider binding cavities, consistent with the need for expanded pockets to accommodate their size...This work provides a structural framework to support the design of conformation-selective inhibitors of P-gp. By integrating conformational diversity with systematic docking, our study contributes to a more mechanistic understanding of P-gp modulation at the molecular level and may help guide the future design of more effective and selective P-gp inhibitors aimed at overcoming P-gp-mediated drug resistance."

Journal • ABCB1

Application of a Modified In Situ Perfusion Model to Quantify Intestinal Drug Excretion and Transporter-Mediated Interactions after Intravenous Administration. (PubMed, AAPS J) - "Here, we employed a modified rat in situ intestinal perfusion model to examine of the drug clearance of apixaban, talinolol, and irinotecan in the short time drug recovery study. The influence of specific efflux transporter inhibitors, including P-glycoprotein (P-gp) inhibitor elacridar, multidrug resistance-associated protein 2 (Mrp2) inhibitor MK571, and breast cancer resistance protein (Bcrp) inhibitor KO143, on IE, systemic exposure and metabolite ratio were accessed using a 2.5-h constant-rate intravenous infusion...The modified perfusion model provides a robust framework for characterizing intestinal clearance and assessing transporter-mediated interactions for drugs undergoing intestinal clearance following i.v. administration. Similar to other routes, intestinal clearance can be a critical elimination pathway, and apixaban is a suitable reference "victim" drug for intestinal clearance inhibition studies."

Journal • Breast Cancer • Oncology • Solid Tumor

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