Delving into the Latest Updates on Elacridar with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Elacridar hydrochloride (USAN)

+ [6]

Target

ABCG2 x P-gp

Action

inhibitors

Mechanism

ABCG2 inhibitors(Broad substrate specificity ATP-binding cassette transporter ABCG2 inhibitors), P-gp inhibitors(P-glycoprotein 1 inhibitors)

Therapeutic Areas

Neoplasms

Active Indication

Neoplasms

Inactive Indication-

Originator Organization

GSK Plc

Active Organization

Chiba University

Inactive Organization

GSK Plc

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC34H33N3O5

InChIKeyOSFCMRGOZNQUSW-UHFFFAOYSA-N

CAS Registry143664-11-3

OBJECTIVEThe placenta is a vital organ for exchanging nutrients, endogenous substances, and xenobiotics between mother and fetus. The syncytiotrophoblast (ST) is crucial in maintaining the placental barrier. Human trophoblast stem cells (hTSCs) have been recently established; however, their utility in studying placental transport functions has not been fully elucidated. This study investigated the expression and function of transporters in hTSC-derived ST cells.METHODSTS^CT cells, as hTSCs, were differentiated into ST-like cells (ST-TS^CT), and the gene expression of 84 transporters in ST-TS^CT cells was evaluated using a PCR array. BeWo cells, a widely used trophoblast model, were used for comparison. BeWo cells were differentiated into ST-like cells using forskolin [BeWo (FK)]. The protein levels of efflux transporters were examined by western blotting, and functional assays were performed using typical fluorescent substrates.RESULTSTransporter gene expression levels were higher in ST-TS^CT than in BeWo (FK) cells, with 27 genes showing more than a 3-fold increase. Ten of these genes were exclusively expressed in ST-TS^CT. Western blotting revealed the presence of efflux transporters, including P-glycoprotein (P-gp/ABCB1), breast cancer resistance protein (BCRP/ABCG2), and multidrug resistance-associated protein 2 (MRP2/ABCC2). Furthermore, the accumulation of typical substrates (Rhodamine123 for P-gp, Hoechst33342 and BODIPY™ FL Prazosin for BCRP, and 5(6)-carboxy-2',7'-dichlorofluorescein diacetate for MRP) significantly increased when transporter inhibitors (elacridar, Ko143, and MK571) were applied.CONCLUSIONThis study showed higher transporter expression in ST-TS^CT than that in a traditional trophoblast model. Furthermore, the functional expression of efflux transporters was observed. ST-TS^CT is valuable for investigating placental transport functions.

01 May 2025·Drug Metabolism and Disposition

In vitro assessment of ATP-binding cassette transporters and their functional genetic polymorphisms on fluoroquinolone accumulation in human embryonic kidney 293 recombinant cell lines

Article

Author: Elens, Laure ; Mahieu, Gwenaëlle ; Van Bambeke, Françoise ; Haufroid, Vincent

Fluoroquinolone tissue distribution and cellular accumulation are hindered by efflux transporters, including ATP-binding cassette subfamily B member 1 (ABCB1), ATP-binding cassette subfamily G member 2 (ABCG2), and ATP-binding cassette subfamily C member 4 (ABCC4). Genetic polymorphisms (single-nucleotide polymorphisms) can impact transporter activity, leading to interindividual variability in the systemic and cellular pharmacokinetics of their substrates. 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)]. Recombinant human embryonic kidney (HEK) cell lines overexpressing wild-type or variant transporters were generated via stable plasmid transfection. The impact of transporter overexpression on fluoroquinolone cell disposition was assessed through accumulation experiments in the presence of specific inhibitors to establish the link between transporter expression and differential accumulation. 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. ABCG2 had no impact. ABCC4 markedly reduced CIP accumulation by 25%, even at the basal level, an effect reversed by MK517. Contrarily to the wild-type and the c.1199A carriers, ABCB1 CGT and TTT variants did not reduce antibiotic accumulation. In conclusion, moxifloxacin and CIP are substrates of the wild-type and 1199G>A ABCB1, while CGT and TTT haplotypes had a marginal impact on fluoroquinolone transport by ABCB1. CIP is a preferential ABCC4 substrate. Because of the large body distribution of these transporters, our findings may help rationalize their role and the impact of their polymorphisms in fluoroquinolone disposition in tissues and cells. SIGNIFICANCE STATEMENT: This study demonstrates that moxifloxacin and ciprofloxacin are substrates of ABCB1, with ciprofloxacin also transported by ABCC4. 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.

14 Apr 2025·ChemMedChem

ABT, Elacridar and Bile‐Duct Cannulated Rats: Tools to Understand Pharmacokinetics

Review

Author: Ouvry, Gilles

AbstractOptimizing pharmacokinetics is an integral part of drug design, albeit a lesser understood one from the medicinal chemist's perspective. 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.

100 Deals associated with Elacridar

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External Link

KEGG	Wiki	ATC	Drug Bank
D03968	-	-	DB04881

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Preclinical	Canada	-	-
Neoplasms	Preclinical	-	GSK Plc	-
Neoplasms	Preclinical	Europe	-	-
Neoplasms	Preclinical	United States	-	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


P10.21.A (EANO2023)	Not Applicable	Brain Cancer	-	Elacridar	ikytllglnz(wubgtigagc) = batjqvwehg dqdfaqhhla (lretpszrzh )	-	08 Sep 2023
EANM2016	Not Applicable	P-glycoprotein	3	Elacridar	tsjjkyiirm(onvpomstao) = ufqdcwgwlp nkmnhmkcrg (edeodwkvrf )	Positive	21 Sep 2016
EANM2016	Not Applicable	P-glycoprotein	3	High-dose Erlotinib	tsjjkyiirm(onvpomstao) = kgwrlasget nkmnhmkcrg (edeodwkvrf )	Positive	21 Sep 2016
SNMMI2016	Not Applicable	-	-	High dose erlotinib	wfvoqhayjy(bclfejwgrr) = tpiytncivp jpwwufzitq (ioobtzleef, 0.03)	-	24 May 2016
SNMMI2016	Not Applicable	-	-	Elacridar	wfvoqhayjy(bclfejwgrr) = nqoxoeziho jpwwufzitq (ioobtzleef, 0.35)	-	24 May 2016
ASCO2004	Phase 1	Advanced cancer	23	Topotecan 2 mg + Elacridar 100 mg	zjumlupsyn(usjyywldrv) = DLTs consisting of CTC Grade 4 leukocytopenia, neutropenia and thrombocytopenia were observed at 2.5 mg/d of topotecan. daqyrpgmsg (coeqrsdgzc ) View more	-	15 Jul 2004