elacridar (GF120918) / GSK - LARVOL DELTA

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

Development and validation of an LC-MS/MS method for simultaneous quantification of eight drugs in plasma and brain: Application in a pharmacokinetic study in mice. (PubMed, J Chromatogr B Analyt Technol Biomed Life Sci) - "A selective and sensitive liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous quantitation of a cassette of 8 drugs, including docetaxel, erlotinib, loperamide, riluzole, vemurafenib, verapamil, elacridar and tariquidar. Similarly, the precision for all compounds at three different concentration levels ranged below 15 %, with the exception of tariquidar in mouse plasma and brain homogenate and riluzole in brain homogenate. Pilot studies have confirmed that the method is suitable for the analysis of mouse plasma samples and brain homogenates following cassette dosing of this mixture in mice."

Journal • PK/PD data • Preclinical

Brain Exposure to the Macrocyclic ALK Inhibitor Zotizalkib is Restricted by ABCB1, and Its Plasma Disposition is Affected by Mouse Carboxylesterase 1c. (PubMed, Mol Pharm) - "Zotizalkib (TPX-0131), a fourth-generation macrocyclic anaplastic lymphoma kinase (ALK) inhibitor, is designed to overcome resistance due to secondary ALK mutations in non-small cell lung cancer (NSCLC)...ABCB1-mediated efflux of zotizalkib was completely inhibited by elacridar, a dual ABCB1/ABCG2 inhibitor, increasing brain exposure without any signs of acute CNS-related toxicities...Notably, the hepatic expression of human CES1 did not affect zotizalkib plasma exposure or tissue distribution. The obtained pharmacokinetic insights may be useful for the further development and optimization of therapeutic efficacy and safety of zotizalkib and related compact macrocyclic ALK inhibitors."

Journal • Preclinical • CNS Disorders • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCB1 • ABCG2 • ALK • CYP3A4 • SLCO1C1

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

Targeting lysosomes by design: novel N-acridine thiosemicarbazones that enable direct detection of intracellular drug localization and overcome P-glycoprotein (Pgp)-mediated resistance. (PubMed, Chem Sci) - "The anti-proliferative activity of NATs against multiple Pgp-positive cancer cell-types (colon, lung, and cervical carcinoma) was abrogated by the third generation Pgp inhibitor, Elacridar, and also Pgp siRNA that down-regulated Pgp...High Pgp expression in KBV1 (+Pgp) cells resulted in co-localization of NATs with the lysosomal marker, LysoTracker™, that was significantly (p < 0.001) greater than the positive control, the di-2-pyridylketone-4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) Zn(ii) complex, [Zn(DpC)2]. Incorporation of acridine into the thiosemicarbazone scaffold led to Pgp-mediated transport into lysosomes to overcome Pgp-resistance."

Journal • Cervical Cancer • Colon Cancer • Oncology • Solid Tumor

The metabolic activation of and platelet response to vicagrel vary with P-glycoprotein deficiency, rather than P-glycoprotein inhibition, in mice. (PubMed, Xenobiotica) - "Moreover, WT mice were administered vicagrel alone or in combination with elacridar (a potent P-gp inhibitor) to determine drug-drug interactions.Compared with WT mice, P-gp KO mice exhibited significant increases in the systemic exposure of H4, the protein expression levels of intestinal Aadac and Ces2, and inhibition of ADP-induced platelet aggregation by vicagrel. However, the H4 exposure was positively correlated with intestinal Aadac protein expression levels but did not vary with short-term inhibition of P-gp efflux activity by elacridar.P-gp-deficient mice, rather than elacridar-treated mice, exhibited significant upregulation of intestinal Aadac and Ces2 and thus, enhanced metabolic activation of and platelet response to vicagrel, suggesting that the metabolic activation of vicagrel may vary with P-gp deficiency, not P-gp inhibition, in mice."

Journal • Preclinical • AADAC

Lenacapavir Exhibits Atropisomerism - Mechanistic Pharmacokinetics and Disposition Studies of Lenacapavir Reveal Intestinal Excretion as a Major Clearance Pathway. (PubMed, J Pharmacol Exp Ther) - "Coadministration of oral elacridar, a P-gp inhibitor, in rats decreased CL and IE of LEN. Due to an atropisomeric interconversion rate that significantly exceeds the in vivo elimination rate, the atropisomer ratio of LEN remains constant in circulation. The disposition of LEN highlights that intestinal excretion has a substantial part in the elimination of compounds that are metabolically highly stable and efflux transporter substrates."

Journal • PK/PD data • Human Immunodeficiency Virus • Infectious Disease